No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GALNT12 encodes a member of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family, enzymes that initiate O-linked glycosylation by transferring N-acetylgalactosamine (GalNAc) to serine or threonine residues on proteins. These glycosylation modifications are important for the proper function of many cellular proteins. Mutations in this gene are associated with increased susceptibility to colorectal cancer, indicating a role in colorectal cancer predisposition.
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 supporting strength: REVEL 0.214 is below the <=0.29 BP4 threshold.
VUS: BP4 (supporting) from REVEL 0.214 is the only met criterion and does not satisfy any generic ACMG/AMP benign or pathogenic combination threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 29 / 1,614,052 alleles. Recorded AF 1.79672e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.19432e-05; MAF= 0.00119%, 3/251188 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.214. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV66662243, n = 6 times).
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: 1 met · 8 not met · 15 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No GALNT12-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP framework was used.
The exact variant is NM_024642.5:c.1201C>T (p.Arg401Cys) in GALNT12.
The available colorectal cancer cohort paper did not explicitly report this exact variant, and the ClinVar record contains no expert-panel classification.
This is a missense variant; REVEL is the only applicable computational path for PP3 and BP4.
REVEL 0.214 does not meet PP3 but meets supporting BP4 under the supplied generic ClinGen SVI thresholds.
No governing GALNT12 VCEP or gene-specific framework is available; the supplied generic ACMG/ClinGen-SVI population defaults were used.
Population data do not meet the supplied PM2 threshold after ancestry-specific frequencies are considered; BA1 and BS1 are not met, and BS2 cannot be established from unphenotyped population counts alone.
No criteria match.
The variant is a missense substitution, so BP4 must be assessed using the missense REVEL path only. REVEL is 0.214, meeting the supplied generic ClinGen SVI supporting BP4 threshold of <=0.29; therefore BP4 is met at supporting strength. SpliceAI is not used because its splice-impact prediction is not applicable evidence for a missense variant under the one-path rule. No GALNT12-specific VCEP specification was available, so the supplied generic calibration applies.
The variant is GALNT12 p.Arg401Cys (NM_024642.5:c.1201C>T). The reviewed ClinVar record is an exact record for this variant and reports no expert-panel interpretation or comparator variant at the same amino-acid position. The available literature extraction also did not report this variant or another GALNT12 substitution producing the same amino-acid change. Therefore, PS1 is not met.
No GALNT12-specific VCEP or gene framework was available, and vcep_materials.json contains no domain_tables entry. The case evidence reports that p.Arg401Cys is not in a statistically significant hotspot. No curated critical functional domain or other well-established mutational hotspot covering residue 401 was supplied. Therefore, PM1 is not met.
PM2 is not met under the supplied generic threshold when ancestry is considered conservatively. Although the aggregate AF is 1.19432e-05 in gnomAD v2.1 and 1.79672e-05 in gnomAD v4.1, the highest observed population-specific frequencies are 1.08731e-04 in gnomAD v2.1 East Asian individuals and 1.11393e-04 in gnomAD v4.1 East Asian individuals, both exceeding the supplied PM2 supporting threshold of <= 0.0001. The non-cancer subsets show similarly low aggregate frequencies but do not remove this ancestry-specific threshold exceedance. No governing VCEP specification is available to authorize an aggregate-only PM2 rule.
Apply PM2 at supporting strength only when the applicable population frequency is <= 0.0001; use the highest observed ancestry-specific frequency when evaluating population rarity, which exceeds the threshold here.
The variant is a missense substitution, so PP3 must be assessed using the missense REVEL path only. REVEL is 0.214, which is below the generic ClinGen SVI supporting PP3 threshold of >=0.644; therefore PP3 is not met. SpliceAI is not used because its splice-impact prediction is not applicable evidence for a missense variant under the one-path rule. No GALNT12-specific VCEP specification was available, so the supplied generic calibration applies.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact ClinVar record for NM_024642.5:c.1201C>T (p.Arg401Cys), ClinVar variation 410585, has zero expert-panel submissions and an overall Uncertain significance classification from three clinical laboratories. Therefore, the required expert-panel pathogenic classification is absent.
PP5 applies only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; no such expert-panel classification is present.
BA1 is not met. The highest reported aggregate population frequency is 1.79672e-05 in gnomAD v4.1, with a maximum population frequency of 1.11393e-04 in East Asian individuals; both are far below the generic stand-alone benign threshold of 0.05 from ACMG/AMP 2015 (PMID:25741868). The non-cancer subsets are also below this threshold: 1.26769e-05 in gnomAD v2.1 non-cancer exomes and 1.35206e-05 in gnomAD v3.1 non-cancer genomes.
Apply BA1 when the applicable population allele frequency is >= 0.05; no reported frequency reaches this threshold.
BS1 is not met. The highest reported aggregate frequency is 1.79672e-05 in gnomAD v4.1 and the highest reported population-specific frequency is 1.11393e-04 in East Asian individuals, both below the generic BS1 threshold of 0.01. The non-cancer subset frequencies are likewise below threshold (1.26769e-05 in gnomAD v2.1 non-cancer exomes and 1.35206e-05 in gnomAD v3.1 non-cancer genomes). No GALNT12-specific benign frequency threshold or governing VCEP specification is available.
Apply BS1 when the applicable population allele frequency is >= 0.01; no reported frequency reaches this threshold.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact ClinVar record for NM_024642.5:c.1201C>T (p.Arg401Cys), ClinVar variation 410585, has zero expert-panel submissions and an overall Uncertain significance classification from three clinical laboratories. Therefore, the required expert-panel benign classification is absent.
BP6 applies only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; no such expert-panel classification is present.
No reliable evidence documents that NM_024642.5:c.1201C>T (p.Arg401Cys) arose de novo in an affected proband with confirmed maternity and paternity. The available variant-specific literature extraction reports no case-level segregation or parental-testing results, and ClinVar records only an uncertain-significance classification without usable de novo evidence. PS2 therefore cannot be assessed.
No applicable GALNT12 VCEP or gene-specific functional framework was identified, so generic ACMG/AMP criteria apply. The available literature does not report a variant-specific functional assay for GALNT12 NM_024642.5:c.1201C>T (NP_078918.3:p.Arg401Cys). PMID:28944238 describes targeted sequencing and REVEL-based prediction of other GALNT12 missense variants, not an assay of this variant; PMID:26467025 describes a general scoring system without GALNT12-specific functional results. Therefore, validated functional evidence demonstrating a damaging effect is unavailable and PS3 cannot be assessed.
Generic ACMG/AMP PS3 requires well-established functional studies supporting a damaging effect; no variant-specific functional study is available.
No reliable case-control enrichment or variant-specific affected-case count is available. PMID:28944238 studied 1,231 colorectal cancer cases and 93 controls, but its extraction states that GALNT12 c.1201C>T/p.Arg401Cys was not explicitly reported; the paper only reports two other GALNT12 missense Tier 2 variants. The ClinVar submission text alleging an individual with colorectal cancer is a non-expert laboratory assertion and is not independently supported by the paper extraction, so it cannot establish PS4.
PS4 requires statistically significant enrichment of the exact variant in affected individuals compared with appropriate controls; no verified exact-variant enrichment is available.
No GALNT12-specific VCEP or gene framework is available, so generic ACMG/AMP PM3 principles apply. The available evidence contains no affected-proband observations, phase information, pathogenic or likely pathogenic allele in trans, cis/trans testing, parental testing, or established recessive inheritance context for NM_024642.5:c.1201C>T (p.Arg401Cys). The two fetched publications were reviewed for allelic observations but do not report this exact variant or provide relevant segregation, phase, or compound-heterozygous data. Therefore PM3 cannot be assessed.
Generic ACMG/AMP PM3: evidence that the variant is observed in trans with a pathogenic variant in an affected individual, with strength dependent on the number and quality of such observations.
PM5 requires a pathogenic or likely pathogenic missense variant at the same GALNT12 residue. The supplied evidence contains no curated same-residue comparator at Arg401, and the PM5 candidate artifact explicitly indicates that classic PM5 semantics could not be safely confirmed and that no candidates were collected. The available paper extraction does not report p.Arg401Cys or identify a same-residue comparator. PM5 therefore cannot be assessed from the available evidence.
No reliable evidence documents a presumed de novo occurrence of NM_024642.5:c.1201C>T (p.Arg401Cys) in an affected individual when parental relationships or parental testing are incomplete. The available variant-specific literature extraction contains no such case-level observation, so PM6 cannot be assessed.
No affected relatives carrying NM_024642.5:c.1201C>T (p.Arg401Cys), informative meioses, or cosegregation analysis is documented. The available variant-specific literature extraction reports no segregation result, and no family-level phenotype-genotype data are provided; therefore PP1 cannot be assessed.
PP2 requires evidence that missense variation is a recognized predominant disease mechanism for GALNT12 and that the gene has a low benign missense background. The available evidence establishes only that GALNT12 was included in a colorectal cancer susceptibility sequencing study in which two GALNT12 missense variants were classified as predicted damaging; it does not establish a validated gene-level missense mechanism, missense enrichment, or a low benign missense rate. PP2 cannot be assessed reliably.
The available evidence does not establish a highly specific phenotype for this exact variant in a patient with a GALNT12-related disorder. PMID:28944238 does not explicitly report c.1201C>T/p.Arg401Cys, and its cohort-level colorectal cancer context is not sufficient to demonstrate a distinctive, highly specific phenotype. The ClinVar PP4 signal is a non-expert laboratory assertion and cannot substitute for directly documented phenotype evidence.
PP4 requires a patient phenotype or family history highly specific for the disease associated with the gene; a nonspecific cancer diagnosis without exact-variant documentation is insufficient.
BS2 is not assessed. The variant is observed only as heterozygous alleles in gnomAD and no homozygotes are reported, but gnomAD population samples do not establish that identified carriers are healthy adults assessed for the relevant GALNT12-associated disease, nor do they establish disease prevalence, age-related penetrance, or a sufficiently penetrant dominant disease model. Therefore, the available allele and homozygote counts do not by themselves satisfy BS2.
BS2 requires reliable observation of the variant in healthy adults, or homozygotes for a dominant condition, in a disease model where that observation is informative; population allele counts alone are insufficient here.
No applicable GALNT12 VCEP or gene-specific functional framework was identified, so generic ACMG/AMP criteria apply. The available literature does not report a variant-specific functional assay showing that GALNT12 NM_024642.5:c.1201C>T (NP_078918.3:p.Arg401Cys) has a normal or tolerated functional effect. PMID:28944238 reports sequencing and computational assessment of GALNT12 variants without testing this variant, while PMID:26467025 is a general scoring-method paper with no GALNT12-specific assay data. Consequently, validated functional evidence supporting a benign effect is unavailable and BS3 cannot be assessed.
Generic ACMG/AMP BS3 requires well-established functional studies showing no damaging effect; no variant-specific functional study is available.
No informative unaffected relatives who carry NM_024642.5:c.1201C>T (p.Arg401Cys), and no age- or phenotype-appropriate non-segregation analysis, are documented. The available literature extraction reports no segregation result; absence of family data cannot establish BS4.
BP1 requires an established disease mechanism in which GALNT12 pathogenic variation is predominantly truncating rather than missense. The case materials contain literature-only support for a possible GALNT12 loss-of-function context, but no validated gene-specific variant spectrum demonstrating that truncating variants predominate and missense variants are generally benign. The available sequencing paper reports predicted-damaging GALNT12 missense variants and therefore does not establish BP1. BP1 cannot be assessed reliably.
No GALNT12-specific VCEP or gene framework is available, so generic ACMG/AMP BP2 principles apply. The available evidence contains no observation of NM_024642.5:c.1201C>T (p.Arg401Cys) in cis with a pathogenic variant or in trans with a benign variant, and no family, tumor, or specimen-level phasing information is provided. The two fetched publications were reviewed but do not report this exact variant or provide relevant co-occurrence or phase data. Therefore BP2 cannot be assessed.
Generic ACMG/AMP BP2: observation of the variant in trans with a known benign variant or in cis with a pathogenic variant, when phase is established.
No verified evidence shows that this exact variant was found in a patient whose disease has an alternative molecular basis. PMID:28944238 does not explicitly report the exact variant, and the available ClinVar submissions are non-expert uncertain-significance assertions rather than documented alternative molecular diagnoses. Accordingly, BP5 cannot be assessed as met from the available case evidence.
BP5 requires the exact variant to be observed in a patient with an alternative molecular basis for the phenotype; no qualifying documented observation is available.
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 GALNT12, mapped onto the exon structure of NM_024642.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| East Asian5 / 44,886 | 0.00011 |
| Remaining individuals3 / 62,482 | 4.8e-05 |
| South Asian2 / 91,084 | 2.2e-05 |
| European (non-Finnish)18 / 1,180,042 | 1.5e-05 |
| African/African American1 / 74,918 | 1.3e-05 |
| East Asian2 / 18,394 | 0.00011 |
| South Asian1 / 30,616 | 3.3e-05 |
This variant is present in gnomAD v4.1 (AF= 1.79672e-05; MAF= 0.00180%, 29/1614052 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000111393; MAF= 0.01114%, 5/44886 alleles, homozygotes = 0); grpmax FAF= 4.345e-05.
This variant is present in gnomAD v2.1 (AF= 1.19432e-05; MAF= 0.00119%, 3/251188 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, so BP4 must be assessed using the missense REVEL path only. REVEL is 0.214, meeting the supplied generic ClinGen SVI supporting BP4 threshold of <=0.29; therefore BP4 is met at supporting strength. SpliceAI is not used because its splice-impact prediction is not applicable evidence for a missense variant under the one-path rule. No GALNT12-specific VCEP specification was available, so the supplied generic calibration applies.
The variant is a missense substitution, so PP3 must be assessed using the missense REVEL path only. REVEL is 0.214, which is below the generic ClinGen SVI supporting PP3 threshold of >=0.644; therefore PP3 is not met. SpliceAI is not used because its splice-impact prediction is not applicable evidence for a missense variant under the one-path rule. No GALNT12-specific VCEP specification was available, so the supplied generic calibration applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.214. BayesDel score = -0.250434.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
We describe a standardized, rules‐based system for evaluating variant pathogenicity in a diagnostic clinical laboratory.
Discussion
Several genes had few predicted damaging variants, including those with one (AXIN2, BUB1, CDKN1B, CDKN2A, SMAD2, TGFB1, and TGFBR1), two (AXIN1, BLM, BMPR1A, FLCN, GALNT12, PTEN, and SMAD3), or three (BMP4, SMAD1, and SMAD4).
Results, Tier 2 variants; Methods, Custom capture gene selection and REVEL scores for missense variants
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= 1.79672e-05; MAF= 0.00180%, 29/1614052 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000111393; MAF= 0.01114%, 5/44886 alleles, homozygotes = 0); grpmax FAF= 4.345e-05.
This variant is present in gnomAD v2.1 (AF= 1.19432e-05; MAF= 0.00119%, 3/251188 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 410585)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.214. BayesDel score = -0.250434.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66662243, n = 6 times).
This variant does not lie in a statistically significant hotspot.