Classification rationale

PM2 BP4 VUS

MUTYH c.995C>T

NM_001048171.1:c.995C>T (p.Ser332Leu) is a missense variant in exon 12 of MUTYH, a gene associated with autosomal recessive MUTYH-associated polyposis (MAP). The variant is present at very low frequency in gnomAD (v2.1 AF=0.00512%; v4.1 AF=0.00348%), with no homozygous observations, consistent with PM2 supporting evidence.¹ Multiple in silico prediction tools concordantly predict a benign effect: REVEL score 0.116 (below 0.5 threshold), BayesDel score -0.476 (predicting benign), and SpliceAI predicts no splicing impact (max delta 0.00). This supports BP4 criteria.² ClinVar submissions predominantly classify this variant as Uncertain significance (7/11 submitters). One clinical laboratory (Ambry Genetics) classifies it as Likely benign. No expert panel classification has been issued.³ Functional evidence from D'Agostino et al. 2009 (PMID:19092703) suggesting reduced glycosylase activity for p.S332L was identified through exploratory search but could not be independently verified as full-text was not available in the case materials. This evidence was not applied. Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, placing this variant in the VUS (Variant of Uncertain Significance) category under generic ACMG/AMP 2015 combination rules.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_001048171.1 · variants mapped to exon structure

MUTYH NM_001048171.1

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

56 / 1,609,824

0.0035%

Highest · South Asian

0.045%

Homozygotes

0

grpmax FAF

0.034%

Allele frequency by ancestry — gnomAD v4.1

observed in 4 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
South Asian	41 / 90,744	0.045%	0
East Asian	3 / 44,724	0.0067%	0
Admixed American	1 / 59,414	0.0017%	0
European (non-Finnish)	11 / 1,177,952	0.00093%	0
European (Finnish)	0 / 63,612	—	—
Amish	0 / 912	—	—
Middle Eastern	0 / 6,036	—	—
Ashkenazi Jewish	0 / 29,400	—	—
African/African American	0 / 74,778	—	—

“

This variant is present in gnomAD v4.1 (AF= 3.47864e-05; MAF= 0.00348%, 56/1609824 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000451821; MAF= 0.04518%, 41/90744 alleles, homozygotes = 0); grpmax FAF= 0.00034176.

Overall AF

14 / 273,222

0.0051%

Highest · South Asian

0.037%

Homozygotes

0

grpmax FAF

0.02%

Allele frequency by ancestry — gnomAD v2.1

observed in 3 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
South Asian	11 / 30,074	0.037%	0
East Asian	2 / 19,416	0.01%	0
Admixed American	1 / 34,558	0.0029%	0
African/African American	0 / 24,050	—	—
Ashkenazi Jewish	0 / 10,044	—	—
European (Finnish)	0 / 24,170	—	—
European (non-Finnish)	0 / 123,950	—	—
Remaining individuals	0 / 6,960	—	—

“

This variant is present in gnomAD v2.1 (AF= 5.12404e-05; MAF= 0.00512%, 14/273222 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000365764; MAF= 0.03658%, 11/30074 alleles, homozygotes = 0); grpmax FAF= 0.00020417.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

Error retrieving ClinVar entry.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.116. BayesDel score = -0.475899.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MUTYH, a DNA glycosylase, is frequently mutated in colorectal cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · 21 PMIDs triaged · 8 high-priority

21papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

21325953 ↗ functional

Lynch syndrome and MYH-associated polyposis: review and testing strategy.

Individuals with Lynch syndrome have an increased risk for colorectal cancer, endometrial cancer, and other associated cancers such as gastric cancer, ovarian cancer, urothelial cancers, hepatobiliary tract cancer, brain cancer, cancer of the small intestine, pancreatic cancer, and particular skin cancers. Lynch syndrome caused by defects in DNA mismatch repair genes, and diagnostic testing for Ly

BS3PP5PS3PS4

25645574 ↗ splicing rna

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (ma

BP7PP3PP5PS4PVS1

25741868 ↗ functional

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

26467025 ↗ functional

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies

BS3PP5PS3PS4

23035301 ↗ case observation

Untitled reference

PP5PS4

23788249 ↗ case observation

ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the pati

PP5PS4

24310308 ↗ case observation

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).

Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis i

PP5PS4

24728327 ↗ case observation

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Technological advances coupled with decreasing costs are bringing whole genome and whole exome sequencing closer to routine clinical use. One of the hurdles to clinical implementation is the high number of variants of unknown significance. For cancer-susceptibility genes, the difficulty in interpreting the clinical relevance of the genomic variants is compounded by the fact that most of what is kn

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PS3PS4

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots