No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MBD4 encodes a DNA glycosylase that detects and repairs deaminated methyl-cytosines in DNA, using a methyl-CpG binding domain to anchor to methylated DNA and a glycosylase domain to carry out mismatch repair in CpG-rich regions. The protein also helps repress transcription from methylated gene promoters. MBD4 acts as a tumor suppressor, and its loss has been linked to colorectal cancer, acute myeloid leukemia, and uveal melanoma.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Met at strong: gnomAD v4.1 grpmax filtering AF of 1.047% exceeds the 1% BS1 threshold (South Asian AF 1.10%).
Met at supporting strength: MBD4-associated disease is caused primarily by truncating loss-of-function variants, and no MBD4 missense variant has reached established pathogenic status.
Met at moderate strength: REVEL 0.178 is at or below the 0.183 moderate BP4 threshold for this missense variant.
Likely Benign: BS1 (strong, gnomAD v4.1 grpmax AF 1.047%) plus BP4 (moderate, REVEL 0.178) and BP1 (supporting) satisfy the generic ACMG benign combination rules.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 11,588 / 1,613,132 alleles. Recorded AF 0.00718354. Recorded homozygote count 71.
This variant is present in gnomAD v2.1 (AF= 0.005111; MAF= 0.51110%, 1444/282528 alleles, homozygotes = 12) and has highest observed frequency in the South Asian population (AF= 0.00970208; MAF= 0.97021%, 297/30612 alleles, homozygotes = 7); grpmax FAF= 0.00879484.
This variant is present in gnomAD-Canada v1.0 (AF= 0.006622516556291391, 122/18422 alleles, homozygotes = 0).
Recorded REVEL score: 0.178. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Likely benign · 2 Uncertain significance · 2 Benign · 1 Likely Benign. ClinVar API review status: criteria provided, conflicting classifications.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 13 not met · 8 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Group scope: PS1, PM1, PM5, PP2 and BP1 - the codon/residue/domain-of-mechanism criteria for NM_001276270.2:c.1684G>C (MBD4, NP_001263199.1:p.Asp562His), a missense change; the variant's REVEL (0.178) and SpliceAI (max delta 0.017) values belong to the PP3/BP4 groups and were not used here.
No ClinGen VCEP/CSPEC specification and no local gene framework exist for MBD4 (cspec not found; final classification framework source generic_acmg_fallback), and vcep_materials.domain_tables contains no MBD4 entry, so all five criteria were adjudicated against generic ACMG/AMP 2015 definitions (PMID:25741868) with no gene-specific thresholds or approved domain boundaries.
PS1 and PM5 are both not met at the codon/residue level: a gene-level ClinVar review finds only two records involving codon 562 - this variant (c.1684G>C, p.Asp562His, conflicting, benign-leaning, 1 star) and c.1686C>T (p.Asp562=, synonymous, Benign/Likely benign). No alternative nucleotide change encodes p.(Asp562His) (PS1 unmet) and no different amino acid change at codon 562 has been established pathogenic (PM5 unmet); the gene's pathogenic variant spectrum is truncating, with its rare missense entries conflicting.
PM1 is not met on both generic prongs: Cancer Hotspots reports no statistically significant hotspot for MBD4 D562 and COSMIC has no record for this variant, while the codon and residue demonstrably tolerate benign variation (benign/likely benign ClinVar classifications; 12 homozygotes at gnomAD v2.1 AF 0.005111 and 71 homozygotes at gnomAD v4.1 AF 0.007183).
PP2 is not met (MBD4 disease is attributed to loss-of-function/truncating variants and no gene-level missense-constraint metric is available in this case), while its mirror-image benign criterion BP1 is met at supporting strength for this missense variant in a truncating-driven gene.
Net contribution to the case classification: no pathogenic-direction points from this group (PS1, PM1, PM5, PP2 all not met) and one supporting benign point (BP1).
Group scope: PS3 and BS3 only — both require well-established in vitro or in vivo functional studies, one showing a damaging effect (PS3) and one showing no damaging effect (BS3) on MBD4 gene product function (ACMG/AMP 2015, PMID:25741868).
No functional assay evidence of any kind exists for MBD4 c.1684G>C p.(Asp562His) in this case: ClinVar (8 submissions, 0 criterion leads), OncoKB (not classified), COSMIC (no record) and Cancer Hotspots (not a significant hotspot) provide none, and the five fetched full texts are policy/guideline documents unrelated to MBD4.
Consequently both PS3 and BS3 are returned as not_assessed; the unmet requirement is the assay itself, not a negative or positive experimental result.
All variant-level quantitative data available in this case (REVEL 0.178, BayesDel -0.306477, SpliceAI max delta 0.017) are computational predictions and belong to the PP3/BP4 and in-silico splicing groups, not to the functional-evidence criteria.
No MBD4-specific ClinGen VCEP/CSPEC specification or local gene framework was found, so generic ACMG/AMP definitions of PS3/BS3 were used without gene-specific strength calibration.
No CSPEC or VCEP specification exists for MBD4 and no local gene framework was found, so these five criteria were adjudicated against generic ACMG/AMP 2015 definitions (PMID:25741868); no gene-specific numeric threshold applies to PS4 or BP5 in this group, and no threshold-direction inequality was evaluated.
PP5 and BP6 both fail on eligibility rather than on direction: the exact-variant ClinVar record VCV000218624 contains zero expert-panel submissions. All seven germline submissions are ordinary single-submitter clinical laboratories (review status 'criteria provided, conflicting classifications', 1 star), so neither the benign-leaning aggregate majority (Likely benign 3, Benign 2) nor the VUS minority may be used.
PS4 is not met: no case-control or cohort enrichment evidence for MBD4 c.1684G>C (p.Asp562His) exists in the retrieved literature, the papers triaged to PS4 are unrelated newborn-screening/DTC-testing policy documents with no MBD4 content, and the variant is present in gnomAD v2.1 at AF 0.005111 with 12 homozygotes, which is inconsistent with enrichment in affected cases.
PP4 and BP5 are not_assessed because the case supplies no proband phenotype (PP4) and no proband genotype/co-occurring variant data (BP5); ClinVar's condition labels for this variant are non-specific ('Inborn genetic diseases', 'not specified') and its submissions carry no usable case-level detail.
Unverified lead recorded for human follow-up: a GeneDx ClinVar submission sentence cites PMID:25504873 and PMID:32421892 for an association with miscarriages and uveal melanoma. Neither PMID is in the source registry, was fetched, or was validated in this case, so it was not used for any criterion.
Allelic group contributes no evidence: neither PM3 nor BP2 is met, because no source in this case documents c.1684G>C phased with another MBD4 variant.
PM3 not met: MBD4 predisposition is autosomal recessive and bi-allelic loss-of-function (PMID:35460607), but the variant was not found in trans with a pathogenic MBD4 variant in any individual; the case is variant-level with no proband genotype or family phasing.
Population data support the absence of a second variant partner rather than an in-trans pairing: gnomAD v2.1 records 1444/282528 alleles (AF 0.511%) with 12 homozygotes and gnomAD v4.1 records 11588/1613132 alleles (AF 0.718%) with 71 homozygotes.
BP2 not met: the trans limb requires a fully penetrant dominant gene/disorder, which MBD4 is not, and the cis limb requires the variant to be on the same allele as a pathogenic MBD4 variant, which is not documented in any source consulted.
Both criteria were assessed against the generic ACMG/AMP 2015 criteria (PMID:25741868) because no ClinGen CSPEC, VCEP specification or local gene-specific framework exists for MBD4; the gene-level recessive inheritance mode was taken from Palles et al. 2022 (PMID:35460607).
One path only: c.1684G>C is a missense substitution (p.Asp562His), so PP3/BP4 were adjudicated entirely on the REVEL protein-impact path; the SpliceAI tie (max delta 0.017) was neither used as support nor as a substitute for a missense predictor.
REVEL 0.178 fails every PP3 band (supporting >= 0.644) and satisfies the moderate BP4 band (<= 0.183) while not reaching strong (<= 0.016): PP3 not met, BP4 met at moderate.
No MBD4 VCEP/CSPEC or gene-specific PP3/BP4 lookup exists, so the generic ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) was applied verbatim; BayesDel was excluded for lack of an established ACMG-strength calibration.
BP7 remains owned by this group's scope list but was not evaluated here because the variant is missense, not synonymous; no truncating/protein-length-changing consequence applies, so no scope exclusion was needed for PP3/BP4.
Population evidence for MBD4 NM_001276270.2:c.1684G>C (p.Asp562His; rs2307293) points consistently toward benignity. The variant is a common missense polymorphism: 0.511% in gnomAD v2.1 (1,444/282,528 alleles) and 0.718% in gnomAD v4.1 (11,588/1,613,132 alleles, 71 homozygotes), with maximum ancestry frequencies of 0.97-1.10% in South Asians, 3.07% in the Amish founder group (28/912) and 4.0% (2/50 alleles) in one v3.1 non-cancer HGDP group.
BS1 is met at strong on the popmax/grpmax metric in the default all-comers source (gnomAD v4.1 grpmax filtering AF 1.047%; South Asian AF 1.104%), although the verdict is boundary-sensitive: cohort-level frequencies are below 1% and the non-cancer/exome-only subsets fall just below the cutoff (v2.1 non-cancer grpmax FAF 0.879%; v3.1 non-cancer grpmax FAF 0.953%), which is why a human-review flag is recorded.
BA1 is not met because no credible population or ancestry group reaches 5%. PM2 is not met because the allele frequency exceeds the 0.0001 supporting threshold by roughly three orders of magnitude in every dataset.
BS2 is not met: although 71 homozygotes are present in gnomAD v4.1 (and 12 in v2.1), BS2 is reserved for disorders in which full penetrance is expected at an early age, and reported germline MBD4 deficiency is an adult-onset, incompletely penetrant cancer predisposition, so the homozygous observations do not qualify as BS2 benign evidence; their benign weight is already captured by BS1.
No Clingen VCEP/CSPEC or local gene-specific framework exists for MBD4 in this case, so generic ACMG/AMP 2015 population thresholds were applied to the all-comers gnomAD v2.1/v4.1 (plus gnomAD-Canada) as the default population sources.
No criteria match.
BS1 (strong benign, allele frequency >=0.01) is met on the popmax/grpmax metric. In gnomAD v4.1 the grpmax filtering AF is 1.04703% (exome grpmax 1.04131%, genome grpmax 0.93567%), above the 1% generic threshold, and the maximum ancestry frequency is South Asian 1.10376% (1,005/91,052 alleles, 18 homozygotes) with the Amish isolate at 3.07% (28/912). gnomAD v2.1 reaches grpmax filtering AF 0.87948% with South Asian AF 0.97021% (297/30,612 alleles), and gnomAD-Canada v1.0 shows South Asian 1.32% (18/1,362 alleles). These values are orders of magnitude above any plausible carrier frequency for MBD4-associated multi-tumor predisposition syndrome, a rare adult-onset cancer predisposition, so the allele frequency is greater than expected for the disorder and BS1 applies at strong. Two caveats are recorded and drive a human-review flag: (1) the cohort-level all-comers frequency is below the cutoff in every dataset (v4.1 0.718%, v2.1 0.511%, v2.1 non-cancer exomes 0.517%, v3.1 non-cancer genomes 0.527%), so the verdict rests on the ancestry-specific popmax/grpmax value, which sits only marginally above 1%; (2) if the analysis were restricted to the non-cancer subsets, the grpmax filtering AFs fall just below the threshold (v2.1 non-cancer exomes 0.879%; v3.1 non-cancer genomes 0.953%) and BS1 would not be met. Because no governing VCEP/cspec specifies a non-cancer or exome-only source for MBD4, the all-comers GNOMAD_V2_1/GNOMAD_V4_1 entries remain the default and BS1 is met at strong.
BS1 (strong benign): allele frequency greater than expected for the disorder, generic threshold >=0.01 (1%), assessed on the popmax/grpmax filtering AF. gnomAD v4.1 grpmax FAF 1.047% (South Asian AF 1.104%) exceeds the threshold, therefore met at strong. Source-dependence of a value this close to the cutoff is flagged for human review.
BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease (ACMG/AMP 2015, Richards et al., PMID:25741868, supporting strength). NM_001276270.2:c.1684G>C in MBD4 is a missense substitution (NP_001263199.1:p.Asp562His), so the variant-type prerequisite is satisfied. The gene's established germline disease mechanism is loss of function: the case's gene-level review (pvs1_gene_context) records lof_mechanism_supported = true, with the supporting germline literature describing a truncating MBD4 variant in a patient with colorectal oligopolyposis and early-onset cancer, and the same review notes that no CSPEC/VCEP exists for MBD4. A gene-level ClinVar review corroborates this: the pathogenic/likely pathogenic MBD4 variant set consists almost entirely of nonsense, frameshift, start-loss, canonical splice and large copy-number (deletion/duplication) variants, whereas the gene's few missense records are conflicting and none of those missense variants has reached established pathogenic status. Consequently missense change is not an established mechanism of MBD4-associated disease, and BP1 is met at its default supporting strength. No gene-specific framework exists to move the strength, and the criterion is benign-direction only.
ACMG/AMP 2015 BP1 (Richards et al., PMID:25741868): missense variant in a gene where primarily truncating variants cause disease; met at supporting strength.
Scope first: c.1684G>C is a missense variant, p.(Asp562His), so BP4 is in scope and is taken from the REVEL path only. The local REVEL v1.3 lookup returns 0.178. Against the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) the BP4 supporting threshold is <= 0.29, moderate <= 0.183 and strong <= 0.016. A score of 0.178 falls at or below 0.183 but above 0.016, so BP4 is met at moderate strength - it does not reach strong. The score is not in a gray zone: 0.178 sits inside the calibrated benign band (<= 0.183), so no fallback to another predictor is warranted or permitted. The SpliceAI max delta of 0.017 was excluded from this determination: it is a splice-path metric and the variant is a missense substitution, so a low splice delta cannot be counted as additional BP4 support and is not double-counted. BayesDel (-0.306477) was likewise not counted, since no generic ACMG-strength BayesDel calibration is established and MBD4 has no VCEP cutoff; treating an uncalibrated score as concordant support would be unsupported. No gene-specific PP3/BP4 lookup was available to override the generic REVEL bands (CSPEC not found; generic_acmg framework mode).
BP4 met at moderate strength: REVEL 0.178 <= 0.183 (ClinGen SVI REVEL moderate BP4 cutoff, PMID:36413997); strong (<= 0.016) not reached.
PS1 requires that a different nucleotide change produce the same amino acid change as an established pathogenic variant (ACMG/AMP 2015, Richards et al., PMID:25741868). MBD4 has no ClinGen VCEP/CSPEC specification and no local gene framework (cspec: not found; final classification framework source = generic_acmg_fallback), so the generic definition governs, and no gene-specific strength calibration exists. A gene-level ClinVar review (E-utilities, db=clinvar, 'MBD4[gene]') finds no other variant that encodes p.(Asp562His): the only records touching codon 562 are VCV000218624 itself (c.1684G>C, p.Asp562His) and VCV002868672 (c.1686C>T, p.Asp562=, Benign/Likely benign, synonymous). The amino acid change p.(Asp562His) therefore has no established pathogenic comparator at all - the single ClinVar record for this exact substitution is a 1-star conflicting record (3 laboratories Likely benign, 2 Benign, 2 Uncertain significance, 0 expert panels) with no pathogenic or likely pathogenic submission. Because no variant sharing this amino acid change has been established as pathogenic, PS1 cannot be met; the criterion is assessed as not met rather than not assessed because absence of any comparator was searched for directly rather than being unexamined.
ACMG/AMP 2015 PS1 (Richards et al., PMID:25741868): same amino acid change as an established pathogenic variant, regardless of nucleotide change; not met - no such comparator exists for p.(Asp562His).
Generic ACMG/AMP 2015 PS4 (PMID:25741868) requires a statistically significant enrichment of the variant in affected cases relative to controls; no CSPEC or VCEP exists for MBD4 (cspec: not found; framework_mode generic_acmg), so no gene-specific PS4 rule and no numeric PS4 threshold or comparison operator exist for this gene. No case-control or case-enrichment study reports MBD4 c.1684G>C (p.Asp562His). The two papers triaged into PS4 (PMID:23169492, a direct-to-consumer genetic testing policy report; PMID:24121147, an alpha-1-antitrypsin newborn-screening workshop) were reviewed in full text and contain no MBD4 content, no mention of p.Asp562His, and no case or cohort data. Population data are inconsistent with case enrichment: the variant is present in gnomAD v2.1 at total AF 0.005111 (1444/282528 alleles, 12 homozygotes), far too common to be an enriched rare disease allele. One GeneDx ClinVar submission sentence states the variant was 'reported in association with multiple miscarriages and with uveal melanoma (pmid: 25504873, 32421892)'; those PMIDs are neither in the source registry nor retrieved/validated in this case, and the statement is an uncontrolled case-observation claim rather than an enrichment measurement, so it cannot support PS4. Because no governing threshold exists for this criterion in this gene, no inequality is evaluated; PS4 is not met for absence of any enriched case series.
PM1 requires the variant to lie in a mutational hotspot and/or a critical, well-established functional domain without benign variation (ACMG/AMP 2015, Richards et al., PMID:25741868). MBD4 has no ClinGen VCEP/CSPEC specification (cspec not found; framework source generic_acmg_fallback) and vcep_materials.domain_tables contains no entry for MBD4, so there is no authoritative, pre-approved list of MBD4 critical domains against which residue 562 could be scored; the generic definition therefore applies. Both generic prongs fail on the evidence available. First, hotspot: the Cancer Hotspots query for MBD4 D562 returned no statistically significant hotspot (search_status no_result) and COSMIC returned no record for c.1684G>C, so there is no somatic or statistical hotspot evidence at this residue. Second, 'without benign variation': codon 562 and its neighbourhood demonstrably tolerate benign variation - the only other ClinVar variant at this codon is c.1686C>T p.Asp562=, classified Benign/Likely benign by multiple submitters; the variant itself is classified Benign or Likely benign by five laboratories and is present in gnomAD v2.1 at AF 0.005111 with 12 homozygotes (7 South Asian) and in gnomAD v4.1 at AF 0.007183 with 71 homozygotes. A region harbouring this much tolerated variation does not satisfy PM1's 'without benign variation' requirement, and residue 562 lies near the C-terminus of the 580-residue protein rather than at a residue demonstrated by any consulted source to be critical. PM1 is not met.
ACMG/AMP 2015 PM1 (Richards et al., PMID:25741868): mutational hotspot and/or critical functional domain without benign variation; generic fallback applied (no MBD4 VCEP/CSPEC; domain_tables empty); not met.
PM2 (supporting, absent or allele frequency <=0.0001) is far from satisfied. This is a common polymorphism (rs2307293): gnomAD v4.1 all-comers AF 0.71835% (11,588/1,613,132 alleles, 71 homozygotes); gnomAD v2.1 all-comers AF 0.51110% (1,444/282,528 alleles, 12 homozygotes); gnomAD v2.1 non-cancer exomes AF 0.51690% (1,223/236,602 alleles); gnomAD v3.1 non-cancer genomes AF 0.52659% (779/147,932 alleles); gnomAD-Canada v1.0 AF 0.66225% (122/18,422 alleles). Every one of these is roughly 5,000-7,000-fold above the 0.0001 supporting threshold. Even the rarest ancestry group with any observations (East Asian, 2/19,952 alleles, AF 0.0100%) is at or above the threshold rather than below it, and the variant is present in the homozygous state many times over. PM2 is not met under the all-comers default or under either non-cancer subset; no source-sensitive analysis can rescue it.
PM2 (supporting pathogenic): allele frequency <=0.0001 in population databases. All datasets are 0.5-0.7%, thousands of times above the threshold, therefore not met.
PM3 is applicable in principle for MBD4 because the associated germline tumor-predisposition phenotype is autosomal recessive and caused by bi-allelic loss-of-function variants (Palles et al. 2022, Am J Hum Genet, PMID:35460607: 'We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4'), and no ClinGen CSPEC or gene-specific VCEP exists for MBD4, so the generic ACMG/AMP 2015 criterion text applies (PMID:25741868). PM3 requires that the variant under assessment be detected in trans with a pathogenic variant in an individual with the recessive disorder. No such observation exists for NM_001276270.2:c.1684G>C (NP_001263199.1:p.Asp562His). The review is variant-level: there is no proband genotype, no family, and therefore no phase determination in this case. ClinVar variation 218624 carries eight submissions (Likely benign x3, Benign x2, Uncertain significance x2, Likely benign x1; 'criteria provided, conflicting classifications'), none from an expert panel, none containing a criterion-level statement about a second MBD4 allele, and the ClinVar-linked literature screened for this variant contains no MBD4 case carrying c.1684G>C. The population datasets record the variant as an allele that occurs on both chromosomes rather than paired with a second variant: gnomAD v2.1 1444/282528 alleles (AF 0.511%), 12 homozygotes (7 in South Asians), and gnomAD v4.1 11588/1613132 alleles (AF 0.718%), 71 homozygotes. In addition, c.1684G>C is a missense change (REVEL 0.178; SpliceAI max delta 0.02) with no loss-of-function support, unlike the truncating bi-allelic variants that define the MBD4 recessive syndrome, so it is not a plausible pathogenic second allele in trans in any case reported. PM3 is therefore not met; the unsatisfied requirement is a documented (likely) pathogenic MBD4 allele on the opposite chromosome, which no source in this case provides.
PM3 (ACMG/AMP 2015, PMID:25741868): for recessive disorders, the variant is detected in trans with a pathogenic variant; MBD4 predisposition is a bi-allelic recessive trait (PMID:35460607), so the criterion is assessed using the generic trans requirement with no gene-specific relaxation.
PM5 requires a different missense change at the same codon as an established pathogenic missense variant (ACMG/AMP 2015, Richards et al., PMID:25741868). MBD4 has no ClinGen VCEP/CSPEC specification and no local gene framework, so the generic definition applies with no gene-specific modification. The case's automatic comparator-harvest artifact (pm5_candidates) explicitly found no candidates and deferred the question to manual review, so a direct gene-level ClinVar review was performed for this adjudication: the only ClinVar records affecting codon 562 are VCV000218624 (the variant itself, NM_001276270.2:c.1684G>C, p.Asp562His) and VCV002868672 (c.1686C>T, p.Asp562=, Benign/Likely benign, synonymous). No missense variant introducing a different amino acid at residue 562 exists in ClinVar, and no established pathogenic MBD4 missense variant exists anywhere in the gene: the gene-level ClinVar set of pathogenic/likely pathogenic MBD4 records is dominated by nonsense, frameshift, start-loss, splice and large copy-number (deletion/duplication) variants, while the rare MBD4 missense entries carry conflicting classifications (e.g. p.Arg14Cys, p.Val46Leu, p.Ser112Asn, p.Arg506Gln). With no pathogenic comparator at codon 562, PM5 is not met.
ACMG/AMP 2015 PM5 (Richards et al., PMID:25741868): different missense change at the same codon as an established pathogenic missense variant; not met - no pathogenic comparator at codon 562.
PP2 requires a missense variant in a gene with a low rate of benign missense variation AND where missense variants are a common mechanism of disease (ACMG/AMP 2015, Richards et al., PMID:25741868). The variant is a missense change (NP_001263199.1:p.Asp562His), so the first prerequisite of the criterion is not the issue; the gene-level conditions fail. The case's gene-level mechanism review (pvs1_gene_context) found the germline MBD4 disease mechanism to be loss of function (lof_mechanism_supported = true), and the ClinVar gene-level record supports that: the pathogenic/likely pathogenic MBD4 variant set is dominated by truncating and copy-number variants, while missense variants in this gene are either conflicting or benign-leaning. Missense variation in MBD4 is therefore not an established disease mechanism. In addition, no gene-level missense constraint metric (e.g. a missense z-score or MPC value) is present anywhere in this case's materials, so even PP2's first prong - a low rate of benign missense variation - cannot be demonstrated for MBD4. A single ClinVar submission (GeneDx, Uncertain significance) asserts that the variant was reported with miscarriages and uveal melanoma and that in-silico analysis supports a deleterious effect; that submission carries no validated PMID trail (its two cited PMIDs were rejected by the audit as unresolved), and neither cited reference mentions this variant, so it is not evidence that missense change is a mechanism in MBD4. PP2 is not met.
ACMG/AMP 2015 PP2 (Richards et al., PMID:25741868): missense variant in a gene with a low rate of benign missense variation where missense is a common mechanism of disease; not met - MBD4 disease mechanism is loss of function, and no missense-constraint metric was available.
Scope first: NM_001276270.2:c.1684G>C is a missense change, NP_001263199.1:p.(Asp562His), so PP3/BP4 are in scope and take evidence from the REVEL protein-impact path alone. VariantValidator places the change in exon 8 of the MANE Select transcript, well inside the coding sequence (exon 8 spans c.1648 to *554), and no splice-region/edge-of-exon annotation is reported. The local REVEL v1.3 lookup returns 0.178. Against the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) the supporting threshold for a deleterious call is >= 0.644, moderate >= 0.773, strong >= 0.932; 0.178 is below all three. PP3 is therefore not met. No gene-specific framework overrides this: ClinGen CSPEC was searched and not found for MBD4 (cspec.found = false), no gene VCEP directory or user-supplied MBD4 framework exists, and framework_mode is generic_acmg. SpliceAI max delta 0.017 is present in the case but is deliberately not used here, because a missense substitution is assessed on the missense path only and a splice prediction is never PP3 support for a missense variant. BayesDel (-0.306477) was also not used: no ACMG-strength generic calibration is established for BayesDel and no MBD4 VCEP cutoff exists, so it is not_available for PP3.
PP3 not met on the missense path: REVEL 0.178 < 0.644 (ClinGen SVI REVEL supporting cutoff, PMID:36413997).
PP5 is applied only for an exact-variant pathogenic or likely pathogenic classification issued by a recognized ClinVar expert panel. ClinVar VCV000218624 (variation 218624) contains zero expert-panel submissions: all 7-8 germline submissions are single-submitter clinical laboratories (ARUP Laboratories, CeGaT, Children's Hospital of Philadelphia, University of Chicago, GeneDx, Ambry Genetics, Labcorp/Invitae), with record review status 'criteria provided, single submitter' and API aggregate review status 'criteria provided, conflicting classifications' at 1 star. No submission carries an expert-panel designation. In addition, the ClinVar aggregate majority for this variant is benign-leaning (Likely benign in 3 laboratories, Benign in 2, Uncertain significance in 2), so even a naive aggregate reading could not support PP5. Literature triaged to PP5 (PMID:23169492, PMID:24121147; and PMID:23652378, PMID:25626707) was checked in full text and contains no MBD4 or p.Asp562His content and no classification. PP5 is therefore not met.
BA1 (stand-alone benign, allele frequency >=0.05) is not met in any dataset. gnomAD v4.1 all-comers: 11,588/1,613,132 alleles, AF 0.718%, 71 homozygotes; the highest ancestry frequency is Amish 3.07% (28/912 alleles, 0 homozygotes) and the grpmax filtering AF is 1.047%. gnomAD v2.1 all-comers: 1,444/282,528 alleles, AF 0.511%, 12 homozygotes; highest ancestry frequency South Asian 0.970% (297/30,612 alleles), grpmax filtering AF 0.879%. gnomAD-Canada v1.0: 122/18,422 alleles, AF 0.662%, within-dataset maximum South Asian 1.32% (18/1,362 alleles), 0 homozygotes. The non-cancer subsets are concordant and lower (v2.1 non-cancer exomes 1,223/236,602, AF 0.517%; v3.1 non-cancer genomes 779/147,932, AF 0.527%). The single figure anywhere near 5% is 4.0% (2/50 alleles, HGDP:RUSSIAN) in the v3.1 non-cancer genomes subset, which rests on 50 alleles and one small isolated cohort and is not a credible stand-alone trigger. No credible population or ancestry group reaches 5%, so the stand-alone benign criterion is not satisfied.
BA1 (stand-alone benign): allele frequency >=0.05 (5%) in a population database. Assessed against all-comers gnomAD v2.1 and v4.1 (defaults, no MBD4 VCEP/CSPEC governing an alternative source) plus gnomAD-Canada v1.0. Highest credible frequency observed is 3.07% (gnomAD v4.1 Amish), therefore not met.
BS2 requires the variant to be observed in a healthy adult individual for a disorder in which full penetrance is expected at an early age (homozygous for a recessive disorder, heterozygous for a dominant one, hemizygous for X-linked). The homozygote data themselves are abundant: gnomAD v4.1 reports 71 homozygotes (68 exome, 3 genome) at AF 0.718%, gnomAD v2.1 reports 12 (9.70%/0.97% in South Asians alone accounting for 7), the v2.1 non-cancer exomes report 12, the v3.1 non-cancer genomes report 3, and the v4.1 South Asian group alone carries 18 homozygotes; gnomAD in principle excludes severe paediatric disease, so these are adult homozygous carriers. However, the qualifier on BS2 is not satisfied. Germline MBD4 deficiency is reported as an adult-onset, cancer-predisposition phenotype (multi-tumor predisposition; the germline case literature in this case reports a 42-year-old with colorectal oligopolyposis and early-onset cancer), i.e. a condition with late onset and incomplete penetrance rather than one in which full penetrance is expected at an early age; the case's germline disease context records no established inheritance model at all. Under those conditions the observation of carriers and homozygotes in a population cohort does not carry the benign weight BS2 is defined to carry, and the benign signal from these homozygotes is already captured by the frequency-based BS1 assessment. BS2 is therefore not met. Flagged for human review because the determination rests on the penetrance/onset character of the disorder rather than on a documented specification, and because a looser reading of BS2 (any homozygous observation in adults) could differ.
BS2 (strong benign): variant observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous) or X-linked (hemizygous) disorder with full penetrance expected at an early age. Homozygotes are present in gnomAD (71 in v4.1), but the disorder is adult-onset and incompletely penetrant, so the qualifier is not satisfied and BS2 is not met.
Generic ACMG/AMP 2015 BP2 (PMID:25741868) is met only when the variant is 'observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern'. Neither limb is satisfied for NM_001276270.2:c.1684G>C (p.Asp562His). The trans limb requires a fully penetrant dominant gene/disorder, which does not describe MBD4: germline MBD4 deficiency is an autosomal-recessive, bi-allelic loss-of-function multi-tumor predisposition syndrome (Palles et al. 2022, PMID:35460607), and monoallelic MBD4 loss-of-function has not been established to cause a fully penetrant dominant phenotype (a Finnish uveal melanoma series of 440 patients found no MBD4 loss-of-function carriers, PMID:32421892, and the recessive model is the reported mechanism). The cis limb requires the variant to be phased on the same allele as a pathogenic variant, and no genotype, family or phasing data exist in this case, which was reviewed at the variant level only. No consulted source places c.1684G>C in cis with a pathogenic MBD4 variant: ClinVar variation 218624 has eight submissions with no expert panel and no phase statements, the literature screened for this variant contains no MBD4 report of it, and aggregate population data are not phase evidence - gnomAD v2.1 shows 12 homozygotes (1444/282528 alleles, AF 0.511%; 7 in South Asians) and gnomAD v4.1 shows 71 homozygotes (11588/1613132 alleles, AF 0.718%), i.e. individuals carrying this variant on both alleles, with no information about a pathogenic variant in cis. BP2 is therefore not met; the unsatisfied requirement is a phase-verified pathogenic MBD4 variant on the same allele (or a setting in which this variant is in trans with a pathogenic allele of a fully penetrant dominant gene).
BP2 (ACMG/AMP 2015, PMID:25741868): observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern; applied generically because no MBD4-specific specification exists.
BP6 is applied only for an exact-variant benign or likely benign classification issued by a recognized ClinVar expert panel. ClinVar VCV000218624 (variation 218624) has zero expert-panel submissions and expert_panel_submissions = 0; every submission is from a single-submitter clinical laboratory and the record review status is 'criteria provided, single submitter' (API aggregate: 'criteria provided, conflicting classifications', 1 star). The aggregate ClinVar signal is benign-leaning (Likely benign in 3 laboratories, Benign in 2, Uncertain significance in 2), but aggregate labels and ordinary laboratory submissions are explicitly not eligible to trigger BP6, so this benign-leaning majority cannot be used. No expert-panel benign assertion exists to cite, therefore BP6 is not met.
PS2 requires a de novo occurrence of the variant in a patient with the disease, with both maternity and paternity confirmed. No such observation exists for MBD4 c.1684G>C (p.Asp562His). The case record contains no proband, no parental genotypes and no pedigree; none of the eight laboratory submissions for ClinVar VCV000218624 asserts de novo status (the full ClinVar record contains zero occurrences of 'de novo'), and neither publication linked to this variant by a submitter (recurrent-triploidy WES candidate report and the Finnish uveal-melanoma MBD4 cohort) reports a confirmed de novo occurrence of this variant. Independently, the allele is far too common in the general population to be a credible rare de novo pathogenic event: gnomAD v2.1 total AF 0.005111 (1444/282528 alleles) with 12 homozygotes, highest in South Asians (AF 0.00970208, 297/30612 alleles, 7 homozygotes), and gnomAD v4.1 AF 0.00718354 (11588/1613132 alleles) with 71 homozygotes, plus gnomAD-Canada v1.0 AF 0.006623 (122/18422 alleles). Status is not_assessed rather than not_met because the criterion cannot be excluded, only unsupported: no trio data (or maternity/paternity-confirmed proband) exist that could ever satisfy it. It would be resolvable only with parental testing in an affected proband, which is not available for this case.
PS2 (generic ACMG/AMP 2015, PMID:25741868): de novo (both maternity and paternity confirmed) in a patient with the disease and no family history - strong evidence for pathogenicity.
PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect on MBD4 (ACMG/AMP 2015, Richards et al., PMID:25741868). No such study exists anywhere in this case's evidence base. MBD4 has no ClinGen VCEP/CSPEC specification (cspec not found; framework_mode = generic_acmg), so generic ACMG/AMP criteria apply. ClinVar variation 218624 carries 8 submissions (Benign, Likely benign, Uncertain significance) but zero criterion leads and no submitter-provided functional evidence; OncoKB lists D562H as not classified with no variant-specific functional or oncogenicity data; COSMIC returns no record for this variant; Cancer Hotspots reports it does not fall in a statistically significant hotspot. All five retrieved full texts (PMID:25741868, 23652378, 25626707, 23169492, 24121147) were screened and none mentions MBD4, c.1684G>C or p.(Asp562His); four are newborn-screening or direct-to-consumer-testing policy documents with no assay content. The only variant-level quantitative data available are computational predictors (REVEL 0.178; BayesDel -0.306477), which are in-silico evidence evaluated under PP3/BP4 and cannot satisfy PS3, which demands a validated assay with appropriate controls and demonstrated biological relevance to MBD4 glycosylase/mismatch-repair function. Because the required class of evidence is absent rather than negative, PS3 is not assessed.
ACMG/AMP 2015 PS3 (Richards et al., PMID:25741868): well-established functional studies showing a damaging effect; not met because no such study exists.
PM6 requires an assumed de novo occurrence (the proband is reported as de novo without confirmation of maternity and paternity) in a patient with the disease. No source in this case makes even an unconfirmed de novo claim for MBD4 c.1684G>C (p.Asp562His): no ClinVar submission for VCV000218624 mentions de novo status, and the two publications a submitter attaches to the variant report no de novo occurrence. There is also no proband or affected individual to anchor the assumption, since the case is a variant-level reanalysis with database evidence only. The allele's population profile further undercuts an assumed de novo pathogenic role: gnomAD v4.1 AF 0.00718354 with 71 homozygotes and gnomAD v2.1 AF 0.005111 with 12 homozygotes (South Asian AF 0.97021%, 7 homozygotes) show an allele that is segregating widely rather than arising anew. PM6 is therefore not_assessed (no assumed-de-novo report exists to assess), not not_met, because the criterion is unmet for absence of the required report rather than for contradicting data.
PM6 (generic ACMG/AMP 2015, PMID:25741868): assumed de novo, without confirmation of paternity and maternity - moderate evidence for pathogenicity.
PP1 requires co-segregation of the variant with disease in multiple affected family members of a gene definitively known to cause the disease. No family genotype data of any kind exist in this case: there is no pedigree, no affected relative genotypes, no meioses counted, and no co-segregation statement in any ClinVar submission for VCV000218624 or in any retrieved publication. The second prerequisite is also unmet on the evidence available here - MBD4 has no ClinGen CSPEC or expert-panel specification, no curated gene-disease validity assertion was retrieved, and the gene-level context record for MBD4 lists no inheritance mode (empty inheritance list) while describing a literature-only association with a multi-tumour predisposition phenotype. With neither family genotypes nor a definitive gene-disease statement, PP1 cannot be evaluated and is recorded as not_assessed; it would be resolvable only by genotyping affected and unaffected relatives and obtaining a co-segregation count.
PP1 (generic ACMG/AMP 2015, PMID:25741868): co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease - supporting evidence for pathogenicity. Strength may be increased with increasing numbers of informative meioses only where a specification permits it; none is available for MBD4.
Generic ACMG/AMP 2015 PP4 (PMID:25741868) requires that the proband's phenotype (or family history) be highly specific for a disease with a single genetic etiology. No proband phenotype, HPO term list, clinical history or family history is present in any case file for this variant; the case provides only the variant, gene and database lookups. The only phenotypic descriptors attached to the variant are the ClinVar condition labels 'Inborn genetic diseases', 'not provided' and 'not specified', which are non-specific and carry no phenotype detail; no ClinVar submission in this record supplies usable clinical features or criteria-level phenotype evidence (evidence_signals empty except an in-silico PP3 statement). Because no phenotype against which specificity could be judged was supplied by the requester, PP4 cannot be evaluated in either direction and is recorded as not_assessed rather than not_met.
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on MBD4 (ACMG/AMP 2015, Richards et al., PMID:25741868). No functional study of any kind was identified for MBD4 c.1684G>C p.(Asp562His). MBD4 has no ClinGen VCEP/CSPEC framework, so generic ACMG/AMP criteria govern. ClinVar variation 218624 shows a benign-leaning submission mix (2 Benign, 4 Likely benign, 2 Uncertain significance laboratories) but exposes no criterion codes and no functional evidence, and the submission audit found zero criterion leads; OncoKB lists the variant as not classified, COSMIC has no record, and Cancer Hotspots places it outside statistically significant hotspots. The five retrieved full texts were screened and none mentions the variant or gene; none reports an MBD4 assay, wild-type-like activity, or any normal-function readout. Computational predictors (REVEL 0.178; BayesDel -0.306477) are in-silico evidence for BP4, not functional assay evidence, and population frequency or benign ClinVar submissions belong to other criteria. With no assay result in either direction, BS3 is not assessed rather than met or refuted.
ACMG/AMP 2015 BS3 (Richards et al., PMID:25741868): well-established functional studies showing no damaging effect; not met because no such study exists.
BS4 requires the observation of lack of segregation - i.e. the variant and the disease do not co-segregate - in affected members of a family. That evidence cannot be assembled here: no pedigree, no affected or unaffected relative genotypes, and no non-segregation observation exist in the case record. The only trace of a non-segregation statement anywhere is the Ambry Genetics ClinVar submission comment for VCV000218624, which reads as a templated menu of possible reasons ('classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease...') and does not state which of these were actually observed; treating that boilerplate as a segregation result would be inferring a criterion from a submitter's final classification, which is not permitted, and it names no family or genotypes. BS4 is therefore recorded as not_assessed rather than not_met: the criterion needs real family genotype data that this case does not contain, and absence of pedigree information is not itself evidence of non-segregation.
BS4 (generic ACMG/AMP 2015, PMID:25741868): observation of lack of segregation in affected members of a family - strong evidence for benignity. Requires actual family genotype data; the mere absence of pedigree information is not a non-segregation observation.
Generic ACMG/AMP 2015 BP5 (PMID:25741868) applies when the variant is found in a patient who has an alternate molecular basis for the disease (for example a pathogenic variant in another gene that explains the phenotype). No proband-level genotype is available: the case contains no co-occurring/compound variant data, no segregation or family information, and no clinical indication, and the ClinVar submissions for this exact variant list no accompanying molecular findings (the submission audit shows empty evidence_signals for six of seven submissions and only an in-silico PP3 statement in the GeneDx submission). With no case in which an alternate causal variant could be identified, BP5 can be neither met nor excluded, so it is recorded as not_assessed.
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
Every interpreted variant in MBD4, mapped onto the exon structure of NM_001276270.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Amish28 / 912 | 0.031 |
| South Asian1005 / 91,052 | 0.01118 hom |
| Ashkenazi Jewish252 / 29,596 | 0.00854 hom |
| European (non-Finnish)9424 / 1,179,718 | 0.00847 hom |
| Remaining individuals488 / 62,470 | 0.00782 hom |
| Middle Eastern41 / 5,994 | 0.0068 |
| Admixed American226 / 60,028 | 0.0038 |
| African/African American91 / 75,022 | 0.0012 |
| European (Finnish)31 / 63,490 | 0.00049 |
| East Asian2 / 44,850 | 4.5e-05 |
| South Asian297 / 30,612 | 0.00977 hom |
| Ashkenazi Jewish87 / 10,368 | 0.0084 |
| Remaining individuals50 / 7,222 | 0.0069 |
| European (non-Finnish)851 / 129,128 | 0.00665 hom |
| Admixed American124 / 35,434 | 0.0035 |
| African/African American23 / 24,958 | 0.00092 |
| European (Finnish)10 / 24,854 | 0.0004 |
| East Asian2 / 19,952 | 0.0001 |
This variant is present in gnomAD v4.1 (AF= 0.00718354; MAF= 0.71835%, 11588/1613132 alleles, homozygotes = 71) and has highest observed frequency in the Amish population (AF= 0.0307018; MAF= 3.07018%, 28/912 alleles, homozygotes = 0); grpmax FAF= 0.0104703.
This variant is present in gnomAD v2.1 (AF= 0.005111; MAF= 0.51110%, 1444/282528 alleles, homozygotes = 12) and has highest observed frequency in the South Asian population (AF= 0.00970208; MAF= 0.97021%, 297/30612 alleles, homozygotes = 7); grpmax FAF= 0.00879484.
This variant is present in gnomAD-Canada v1.0 (AF= 0.006622516556291391, 122/18422 alleles, homozygotes = 0).
Scope first: c.1684G>C is a missense variant, p.(Asp562His), so BP4 is in scope and is taken from the REVEL path only. The local REVEL v1.3 lookup returns 0.178. Against the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) the BP4 supporting threshold is <= 0.29, moderate <= 0.183 and strong <= 0.016. A score of 0.178 falls at or below 0.183 but above 0.016, so BP4 is met at moderate strength - it does not reach strong. The score is not in a gray zone: 0.178 sits inside the calibrated benign band (<= 0.183), so no fallback to another predictor is warranted or permitted. The SpliceAI max delta of 0.017 was excluded from this determination: it is a splice-path metric and the variant is a missense substitution, so a low splice delta cannot be counted as additional BP4 support and is not double-counted. BayesDel (-0.306477) was likewise not counted, since no generic ACMG-strength BayesDel calibration is established and MBD4 has no VCEP cutoff; treating an uncalibrated score as concordant support would be unsupported. No gene-specific PP3/BP4 lookup was available to override the generic REVEL bands (CSPEC not found; generic_acmg framework mode).
BP4 met at moderate strength: REVEL 0.178 <= 0.183 (ClinGen SVI REVEL moderate BP4 cutoff, PMID:36413997); strong (<= 0.016) not reached.
Scope first: NM_001276270.2:c.1684G>C is a missense change, NP_001263199.1:p.(Asp562His), so PP3/BP4 are in scope and take evidence from the REVEL protein-impact path alone. VariantValidator places the change in exon 8 of the MANE Select transcript, well inside the coding sequence (exon 8 spans c.1648 to *554), and no splice-region/edge-of-exon annotation is reported. The local REVEL v1.3 lookup returns 0.178. Against the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) the supporting threshold for a deleterious call is >= 0.644, moderate >= 0.773, strong >= 0.932; 0.178 is below all three. PP3 is therefore not met. No gene-specific framework overrides this: ClinGen CSPEC was searched and not found for MBD4 (cspec.found = false), no gene VCEP directory or user-supplied MBD4 framework exists, and framework_mode is generic_acmg. SpliceAI max delta 0.017 is present in the case but is deliberately not used here, because a missense substitution is assessed on the missense path only and a splice prediction is never PP3 support for a missense variant. BayesDel (-0.306477) was also not used: no ACMG-strength generic calibration is established for BayesDel and no MBD4 VCEP cutoff exists, so it is not_available for PP3.
PP3 not met on the missense path: REVEL 0.178 < 0.644 (ClinGen SVI REVEL supporting cutoff, PMID:36413997).
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.178. BayesDel score = -0.306477.
7 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
We have provided two sets of criteria: one for classification of pathogenic or likely pathogenic variants (Table 3) and one for classification of benign or likely benign variants (Table 4). Each pathogenic criterion is weighted as very strong (PVS1), strong (PS1–4); moderate (PM1–6), or supporting (PP1–5), and each benign criterion is weighted as stand-alone (BA1), strong (BS1–4), or supporting (BP1–6).
Location PROPOSED CRITERIA FOR INTERPRETATION OF SEQUENCE VARIANTS, paragraph 3 (with Tables 3–5; PS1/PM1/PM5/PP2 in Table 3, BP1 in Table 4)
Context Expert-opinion/consensus guideline developed by an ACMG/AMP/College of American Pathologists workgroup (2013-2014), informed by surveys of >100 sequencing laboratories and workshop feedback; not an experimental or cohort study.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00718354; MAF= 0.71835%, 11588/1613132 alleles, homozygotes = 71) and has highest observed frequency in the Amish population (AF= 0.0307018; MAF= 3.07018%, 28/912 alleles, homozygotes = 0); grpmax FAF= 0.0104703.
This variant is present in gnomAD v2.1 (AF= 0.005111; MAF= 0.51110%, 1444/282528 alleles, homozygotes = 12) and has highest observed frequency in the South Asian population (AF= 0.00970208; MAF= 0.97021%, 297/30612 alleles, homozygotes = 7); grpmax FAF= 0.00879484.
This variant is present in gnomAD-Canada v1.0 (AF= 0.006622516556291391, 122/18422 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 218624)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.178. BayesDel score = -0.306477.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.