MUTYH c.714C>T, p.(Asn238=)

Reasoning

PM2 is met at supporting strength. The variant is present at extremely low frequency in the relevant population datasets: gnomAD v2.1 non-cancer exomes AF 8.45902e-06 (2/236,434), gnomAD v3.1 non-cancer genomes AF 5.40709e-05 (8/147,954), and gnomAD v4.1 combined data AF 4.33708e-05 (70/1,613,988). These values are all below the supplied generic PM2 supporting threshold of <=0.0001; the absence of homozygotes is also consistent with a rare recessive allele.

Rule

PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• gnomAD v2.1 non-cancer exomes: 2/236,434 alleles, AF 8.45902e-06, homozygotes 0.
• gnomAD v3.1 non-cancer genomes: 8/147,954 alleles, AF 5.40709e-05, homozygotes 0.
• gnomAD v4.1 combined exome-plus-genome data: 70/1,613,988 alleles, AF 4.33708e-05, homozygotes 0.
• The variant is absent from gnomAD-Canada v1.0, according to the case population evidence.
• Generic SVI PM2 calibration supplied for this interpretation: <=0.0001, supporting strength (ClinGen SVI 2020 recommendation cited in the prompt; ACMG/AMP 2015 criterion definition PMID:25741868).

Sources

Reasoning

The variant is synonymous (NM_001128425.2:c.714C>T; p.(Asn238=)), so the applicable generic PP3/BP4 path is SpliceAI only. SpliceAI max delta is 0.114, below the PP3 supporting threshold of >= 0.2; therefore PP3 is not met. REVEL is not applicable to this synonymous variant, and no other computational predictor is counted.

Rule

PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)

Evidence considered

• NM_001128425.2:c.714C>T is synonymous, producing NP_001121897.1:p.(Asn238=); the generic synonymous-variant path uses SpliceAI only.
• SpliceAI max delta = 0.114 (DS_AG 0.005, DS_AL 0.114, DS_DG 0.007, DS_DL 0.049).
• The supplied generic calibration sets SpliceAI PP3 supporting at >= 0.2; the SpliceAI recommended cutoff is attributed to Jaganathan et al. 2019, Cell (PMID:30661751).

Sources

Reasoning

PP5 is not met because the exact-variant ClinVar record has zero expert-panel submissions. The available assertions are ordinary laboratory submissions, including Likely benign/Benign classifications, and the governing rule explicitly excludes ordinary laboratory submissions, aggregate labels, and non-expert assertions from triggering PP5.

Rule

Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.

Evidence considered

• Exact-variant ClinVar record VCV000184309 reports 0 expert-panel submissions; the record contains single-submitter laboratory assertions, predominantly Likely benign, plus one Benign and one Uncertain significance assertion.
• The ClinVar review status is criteria provided, conflicting classifications, not an expert-panel classification.

Sources

Reasoning

BA1 is not met. The highest reported allele frequency is 0.00049456 (1/2,022 alleles) in the gnomAD v3.1 non-cancer remaining-individuals subgroup; the overall gnomAD v4.1 frequency is 4.33708e-05 (70/1,613,988 alleles), both far below the generic stand-alone threshold of >=0.05. The variant is a synonymous substitution, and the available population observations do not indicate a calling artifact requiring exclusion.

Rule

BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• gnomAD v2.1 overall exomes: 4/250,588 alleles, AF 1.59625e-05, homozygotes 0.
• gnomAD v2.1 non-cancer exomes: 2/236,434 alleles, AF 8.45902e-06, homozygotes 0.
• gnomAD v3.1 non-cancer genomes: 8/147,954 alleles, AF 5.40709e-05, homozygotes 0; highest subgroup AF 0.00049456 (1/2,022 alleles).
• gnomAD v4.1 combined exome-plus-genome data: 70/1,613,988 alleles, AF 4.33708e-05, homozygotes 0; highest subgroup AF 0.000112029 (7/62,484 alleles).
• Generic ACMG/AMP 2015 stand-alone benign allele-frequency calibration supplied for this interpretation: BA1 >=0.05 (PMID:25741868).

Sources

Reasoning

BS1 is not met. The highest observed frequency is 0.00049456 in a small gnomAD v3.1 non-cancer subgroup, while the overall frequencies are 1.59625e-05 in gnomAD v2.1, 5.40709e-05 in gnomAD v3.1 non-cancer genomes, and 4.33708e-05 in gnomAD v4.1. All are below the supplied generic BS1 threshold of >=0.01, and no VCEP-specific threshold is available because the listed MUTYH specification has no released criteria.

Rule

BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)

Evidence considered

• gnomAD v2.1 overall exomes: AF 1.59625e-05 (4/250,588 alleles).
• gnomAD v2.1 non-cancer exomes: AF 8.45902e-06 (2/236,434 alleles).
• gnomAD v3.1 non-cancer genomes: AF 5.40709e-05 (8/147,954 alleles), with highest subgroup AF 0.00049456 (1/2,022 alleles).
• gnomAD v4.1 combined data: AF 4.33708e-05 (70/1,613,988 alleles), with highest subgroup AF 0.000112029 (7/62,484 alleles).
• Generic SVI BS1 calibration supplied for this interpretation: allele frequency >=0.01; no released MUTYH VCEP threshold supersedes it.

Sources

Reasoning

BS2 is not met. MUTYH-related disease is autosomal recessive, so BS2 would require an observed homozygous variant in a healthy adult with early full penetrance expected. The available gnomAD v2.1, gnomAD v2.1 non-cancer, gnomAD v3.1 non-cancer, and gnomAD v4.1 records each report zero homozygotes; therefore no qualifying healthy homozygous observation is present.

Rule

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.

Evidence considered

• The governing disease context identifies autosomal recessive inheritance for MUTYH-related familial adenomatous polyposis 2.
• gnomAD v2.1 overall exomes: homozygotes 0; gnomAD v2.1 non-cancer exomes: homozygotes 0.
• gnomAD v3.1 non-cancer genomes: homozygotes 0; gnomAD v4.1 combined data: homozygotes 0.
• No qualifying healthy adult homozygous observation is reported in the available population datasets.

Sources

Reasoning

The variant is synonymous (NM_001128425.2:c.714C>T; p.(Asn238=)), so the applicable generic PP3/BP4 path is SpliceAI only. SpliceAI max delta is 0.114, above the BP4 supporting threshold of <= 0.1; therefore BP4 is not met. REVEL is not applicable to this synonymous variant, and the SpliceAI result cannot be used as BP4 because it does not meet the cutoff.

Rule

BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)

Evidence considered

• NM_001128425.2:c.714C>T is synonymous, producing NP_001121897.1:p.(Asn238=); the generic synonymous-variant path uses SpliceAI only.
• SpliceAI max delta = 0.114 (DS_AG 0.005, DS_AL 0.114, DS_DG 0.007, DS_DL 0.049).
• The supplied generic calibration sets SpliceAI BP4 supporting at <= 0.1; the SpliceAI recommended cutoff is attributed to Jaganathan et al. 2019, Cell (PMID:30661751).

Sources

Reasoning

BP6 is not met because the exact-variant ClinVar record has zero expert-panel submissions. Although ordinary laboratory submissions report Likely benign or Benign classifications, the governing rule states that ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6.

Rule

Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.

Evidence considered

• Exact-variant ClinVar record VCV000184309 reports 0 expert-panel submissions and a conflicting aggregate record with single-submitter assertions; the available benign assertions are not expert-panel assertions.
• The ClinVar submission audit identifies 13 submissions, 0 expert-panel submissions, and laboratory classifications including Likely benign and Benign.

Sources

Reasoning

BP7 is applicable because NM_001128425.2:c.714C>T is synonymous. However, BP7 requires splice prediction algorithms to predict no impact, and the available SpliceAI max delta is 0.114, exceeding the supplied <= 0.1 no-impact cutoff. The criterion is therefore not met; nucleotide conservation need not be resolved after the splice requirement fails.

Rule

BP7: A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.

Evidence considered

• NM_001128425.2:c.714C>T is synonymous, producing NP_001121897.1:p.(Asn238=), so BP7 is within scope.
• SpliceAI max delta = 0.114 (DS_AG 0.005, DS_AL 0.114, DS_DG 0.007, DS_DL 0.049), which does not satisfy the supplied <= 0.1 no-impact cutoff.
• No nucleotide-conservation result was available; this missing second condition cannot rescue BP7 because the splice no-impact condition is already not met.

Still missing

• No nucleotide-conservation result was located, but it is not outcome-determinative because the splice no-impact requirement already fails.

Sources

Reasoning

PS2 cannot be assessed because the available evidence contains no proband disease documentation, family-history assessment, or testing results confirming both maternity and paternity for NM_001128425.2:c.714C>T.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• The available case evidence contains no proband phenotype, family-history, maternity, or paternity results for NM_001128425.2:c.714C>T.
• Aceto et al. 2005 (PMID:16134147) reports a different synonymous MUTYH variant, c.672C>T, not the evaluated c.714C>T variant, and provides no de novo evidence for the evaluated variant.

Still missing

• Proband disease phenotype and diagnostic documentation
• Family-history assessment
• Maternity confirmation
• Paternity confirmation

Sources

Reasoning

No variant-specific validated in vitro or in vivo functional assay was identified for NM_001128425.2:c.714C>T (MUTYH), which is synonymous, p.(Asn238=). The reviewed exact-variant literature record, PMID:16134147, reports a different synonymous MUTYH variant, c.672C>T (p.Asn224Asn), and does not provide assay results for c.714C>T. Therefore, the evidence does not establish the well-established functional-study support required for PS3; no PS3 strength is assigned.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• Aceto et al. 2005 (PMID:16134147): the exact variant c.714C>T (p.Asn238=) is not mentioned; the paper instead reports synonymous MUTYH c.672C>T (p.Asn224Asn) and provides no variant-specific functional assay result for c.714C>T.
• No variant-specific validated in vitro or in vivo functional study, assay controls, or reproducible clinical-laboratory functional evidence was available for c.714C>T.

Still missing

• A variant-specific in vitro or in vivo assay with appropriate controls and demonstrated biological relevance is needed to assess PS3.

Sources

Reasoning

No case-control study, variant-specific affected-case prevalence, odds ratio, relative risk, or confidence interval was identified for NM_001128425.2:c.714C>T. The governing PS4 threshold is an odds ratio or relative risk >5.0 with a confidence interval that does not include 1.0; no value is available, so the criterion cannot be assessed.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• Aceto et al. 2005 (PMID:16134147) reports a different synonymous MUTYH variant, c.672C>T (p.Asn224Asn), not c.714C>T; it therefore supplies no case-control estimate for this variant.
• No supplied source provides a variant-specific affected-case prevalence, control prevalence, odds ratio, relative risk, or confidence interval for c.714C>T.

Still missing

• Variant-specific case-control affected and control counts or an odds ratio/relative risk with its confidence interval are unavailable.

Sources

Reasoning

MUTYH-associated polyposis is documented as autosomal recessive, so PM3 is applicable in principle. However, the case evidence contains no affected-proband observation for NM_001128425.2:c.714C>T with a second pathogenic MUTYH variant and no parent or offspring testing establishing that this variant is in trans with a pathogenic variant. ClinVar records provide classifications and literature links but no phase or allelic observation; the reviewed exact-variant literature trail does not provide such evidence. Therefore, PM3 cannot be assessed.

Rule

For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.

Evidence considered

• The case framework identifies MUTYH-associated polyposis as autosomal recessive.
• ClinVar variation 184309 contains classification submissions and literature links but no documented parent/offspring phase, in-trans configuration, or affected-proband biallelic observation for NM_001128425.2:c.714C>T.
• Aceto et al. 2005 (PMID:16134147) reports a different synonymous MUTYH variant, c.672C>T (p.Asn224Asn), in a heterozygous patient; the exact variant c.714C>T is not mentioned, so this paper does not establish PM3 evidence for the case variant.

Still missing

• Parent or offspring testing establishing phase with a pathogenic MUTYH variant
• Affected-proband or other clinical observation documenting the variant in trans with a pathogenic MUTYH variant

Sources

Reasoning

PM6 cannot be assessed because the available evidence does not document an assumed de novo occurrence, parental testing, or the proband's disease phenotype for NM_001128425.2:c.714C>T.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• The available case evidence contains no parental testing or de novo observation for NM_001128425.2:c.714C>T.
• Aceto et al. 2005 (PMID:16134147) reports a different synonymous MUTYH variant, c.672C>T, and does not provide de novo evidence for the evaluated variant.

Still missing

• Documented de novo observation in the proband
• Parental testing or stated basis for assuming de novo status
• Proband disease phenotype

Sources

Reasoning

PP1 cannot be assessed because the available evidence contains no affected family members, informative meioses, phenotype-consistent relatives, or segregation results for NM_001128425.2:c.714C>T.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• The available case evidence contains no family pedigree, affected-relative testing, informative meioses, or segregation results for NM_001128425.2:c.714C>T.
• Aceto et al. 2005 (PMID:16134147) describes a different synonymous MUTYH variant in one patient with a reported horizontal family history, not segregation of the evaluated variant.

Still missing

• Affected relatives with phenotype documentation
• Variant testing results in relatives
• Informative meioses and segregation count

Sources

Reasoning

The supplied case evidence contains no patient phenotype or family-history description that can be judged highly specific for a disease with a single genetic etiology. The variant is synonymous, but molecular consequence does not substitute for the phenotype or family-history requirement of PP4.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Evidence considered

• The case materials provide variant normalization and population/ClinVar data but no patient phenotype or family-history evidence for PP4.

Still missing

• Patient phenotype and family-history details, including the suspected disease and diagnostic specificity, are unavailable.

Reasoning

No variant-specific validated in vitro or in vivo functional assay was identified for NM_001128425.2:c.714C>T (MUTYH), which is synonymous, p.(Asn238=). The reviewed exact-variant literature record, PMID:16134147, reports a different synonymous MUTYH variant, c.672C>T (p.Asn224Asn), and does not provide assay results demonstrating no damaging effect for c.714C>T. Therefore, the evidence does not establish the well-established functional-study support required for BS3; no BS3 strength is assigned.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• Aceto et al. 2005 (PMID:16134147): the exact variant c.714C>T (p.Asn238=) is not mentioned; the paper instead reports synonymous MUTYH c.672C>T (p.Asn224Asn) and provides no variant-specific functional assay result for c.714C>T.
• No variant-specific validated in vitro or in vivo functional study, assay controls, or reproducible clinical-laboratory functional evidence was available to demonstrate preserved protein function or splicing for c.714C>T.

Still missing

• A variant-specific in vitro or in vivo assay with appropriate controls and demonstrated biological relevance is needed to assess BS3.

Sources

Reasoning

BS4 cannot be assessed because the available evidence identifies no affected family members who were tested for NM_001128425.2:c.714C>T and therefore provides no valid non-segregation observation.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• The available case evidence contains no tested affected relatives or non-segregation results for NM_001128425.2:c.714C>T.
• Aceto et al. 2005 (PMID:16134147) does not report non-segregation of the evaluated variant; it reports a different synonymous MUTYH variant.

Still missing

• Affected relatives with phenotype documentation
• Variant testing results in affected relatives
• Assessment of phenocopy and possible additional pathogenic variants

Sources

Reasoning

BP2 is applicable in principle because MUTYH-associated polyposis is recessive and the criterion permits an in-cis observation in any inheritance pattern. The case evidence contains no observation of NM_001128425.2:c.714C>T in cis with a pathogenic variant and no observation in trans with a pathogenic variant in a fully penetrant dominant disorder. ClinVar records and the reviewed exact-variant literature do not document either configuration. Therefore, BP2 cannot be assessed.

Rule

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.

Evidence considered

• ClinVar variation 184309 contains classification submissions and literature links but no documented cis or trans co-occurrence for NM_001128425.2:c.714C>T.
• Aceto et al. 2005 (PMID:16134147) reports a different synonymous MUTYH variant, c.672C>T (p.Asn224Asn), and does not mention the exact case variant or provide cis/trans evidence for it.

Still missing

• Phased evidence documenting c.714C>T in cis with a pathogenic variant
• Evidence of c.714C>T in trans with a pathogenic variant in a fully penetrant dominant gene/disorder

Sources

Reasoning

No case-specific evidence shows that NM_001128425.2:c.714C>T was found in a patient with an alternate molecular basis for disease. General disease references and non-expert ClinVar classifications do not establish the BP5 case-level requirement.

Rule

Variant found in a case with an alternate molecular basis for disease.

Evidence considered

• The supplied evidence contains no patient-level alternate molecular diagnosis associated with this exact variant.

Still missing

• A case report or clinical record documenting the variant together with an alternate molecular diagnosis is unavailable.