Submissions for variant NM_001048174.2(MUTYH):c.901G>A (p.Val301Met)

gnomAD frequency: 0.00008  dbSNP: rs147718169

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129011	SCV000172908	likely benign	Hereditary cancer-predisposing syndrome	2020-07-07	criteria provided, single submitter	clinical testing	This alteration is 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 or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205715	SCV000260639	likely benign	Familial adenomatous polyposis 2	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000656910	SCV000292628	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Observed in individuals with colon cancer and/or polyps and other cancers (PMID: 17207658, 25980754, 25186627, 27498913, 27829682, 29684080, 31062380); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.Val315Met and p.Val326Met; This variant is associated with the following publications: (PMID: 19300419, 17207658, 27829682, 27498913, 20571908, 25980754, 24728327, 16879101, 25186627, 29684080, 31062380, 35264596, 33471991, 37013556, 20816984, 36243179, 34326862, 35980532)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000121592	SCV000297028	uncertain significance	not specified	2015-07-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000205715	SCV000487343	uncertain significance	Familial adenomatous polyposis 2	2016-03-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515294	SCV000611408	uncertain significance	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129011	SCV000685684	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 329 of the MUTYH protein. This variant is also known as c.943G>A (p.Val315Pro) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with head and neck cancer, papillary thyroid cancer, colorectal cancer, or breast cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380, 32923874). This variant has also been identified in 23/282826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV000205715	SCV000837757	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656910	SCV000889536	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with suspected MUTYH-associated polyposis (PMID: 2829682 (2016)), Lynch syndrome-associated cancer or polyps (PMID: 25980754 (2015)), breast cancer (PMID: 35264596 (2022)), thyroid cancer (PMID: 29684080 (2018)), and squamous cell carcinoma (PMID: 17207658 (2007)). The frequency of this variant in the general population, 0.00011 (4/35436 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121592	SCV000919793	uncertain significance	not specified	2024-03-20	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.985G>A (p.Val329Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (8.7e-05 vs 0.0046), allowing no conclusion about variant significance. c.985G>A variant has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Yurgelun_2015, Ricci_2016) and Rectal Colon cancer (AlHarbi_2023). This variant was also reported in the control cohort of a large case-control study of Biliary tract cancer (Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37306523, 24728327, 17207658, 36243179, 27829682, 19300419, 20571908, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 134859). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000656910	SCV001961110	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129011	SCV002532350	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000205715	SCV003817133	uncertain significance	Familial adenomatous polyposis 2	2023-03-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000205715	SCV004015250	uncertain significance	Familial adenomatous polyposis 2	2023-07-07	criteria provided, single submitter	clinical testing	A Variant of Uncertain Significance was detected in MUTYH gene. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 329 of the MUTYH protein (p.Val329Met). This variant is present in population databases (rs147718169, gnomAD 0.01%). This variant has been reported in individuals affected with head and neck cancer, papillary thyroid cancer, colorectal cancer, and breast cancer cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380, 32923874). ClinVar contains an entry for this variant (Variation ID: 134859). Computational prediction suggests that this variant impact conflicting (SIFT: "Deleterious"; PolyPhen-2: "Benign"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121592	SCV004024979	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000205715	SCV004835203	uncertain significance	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 329 of the MUTYH protein. This variant is also known as c.943G>A (p.Val315Pro) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with head and neck cancer, papillary thyroid cancer, colorectal cancer, and breast cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380, 32923874). This variant has also been identified in 23/282826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ITMI	RCV000121592	SCV000085788	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656910	SCV000592703	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MUTYH p.Val329Met variant was identified in 4 of 3176 proband chromosomes (frequency: 0.0013) in one individual with squamous cell carcinoma of the head and neck (Gorgens 2007), two individuals with MUTYH-associated polyposis (Ricci 2017) and one individual with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147718169) as “With Uncertain significance, other allele”, ClinVar (uncertain significance by Ambry Genetics, Invitae, GeneDx, Children's Hospital of Philadelphia, Counsyl, Fulgent Genetics, and Color), Clinvitae (4x), and Insight Colon Cancer Gene Variant Database. The variant was not identified in Cosmic, MutDB, or UMD-LSDB databases. The variant was also identified by our laboratory in 1 individual with Lynch Syndrome. The variant was identified in control databases in 23 of 277164 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24018 chromosomes (freq: 0.00008), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 5 of 34420 chromosomes (freq: 0.0001), European (Non-Finnish) in 12 of 126662 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Val329 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.