Submissions for variant NM_001048174.2(MUTYH):c.1172C>A (p.Ala391Asp)

gnomAD frequency: 0.00002  dbSNP: rs369299948

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130546	SCV000185415	likely benign	Hereditary cancer-predisposing syndrome	2022-10-12	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.
Counsyl	RCV000408991	SCV000487363	uncertain significance	Familial adenomatous polyposis 2	2016-06-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000408991	SCV000639261	uncertain significance	Familial adenomatous polyposis 2	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 419 of the MUTYH protein (p.Ala419Asp). This variant is present in population databases (rs369299948, gnomAD 0.005%). This missense change has been observed in individual(s) with several polyps (PMID: 28644590). ClinVar contains an entry for this variant (Variation ID: 141858). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759155	SCV000888301	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130546	SCV000911193	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 419 of the MUTYH protein. This variant is also known as c.1214C>A (p.Ala405Lys) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 8/282514 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.
GeneDx	RCV000759155	SCV001777928	uncertain significance	not provided	2024-05-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal polyps (PMID: 28644590); This variant is associated with the following publications: (PMID: 26580448, 33471991, 30267214, 23108399, 28644590)
Sema4, Sema4	RCV000130546	SCV002532216	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130546	SCV004228094	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987370	SCV004803375	uncertain significance	not specified	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1256C>A (p.Ala419Asp) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of 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 2.4e-05 in 251110 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1256C>A has been reported in the literature in at least one individual with polyps (e.g., McVeigh_2016) and one pediatric case with osteosarcoma (e.g., Zhang_2015). These reports 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: 28644590, 26580448). ClinVar contains an entry for this variant (Variation ID: 141858). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000408991	SCV004843136	uncertain significance	Familial adenomatous polyposis 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 419 of the MUTYH protein. This variant is also known as c.1214C>A (p.Ala405Lys) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 8/282514 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.
Baylor Genetics	RCV000408991	SCV005056065	uncertain significance	Familial adenomatous polyposis 2	2024-01-19	criteria provided, single submitter	clinical testing