Submissions for variant NM_001048174.2(MUTYH):c.409G>A (p.Ala137Thr)

gnomAD frequency: 0.00001  dbSNP: rs201103359

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165474	SCV000216205	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	The p.A165T variant (also known as c.493G>A), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 493. The alanine at codon 165 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228243	SCV000285952	uncertain significance	Familial adenomatous polyposis 2	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 165 of the MUTYH protein (p.Ala165Thr). This variant is present in population databases (rs201103359, gnomAD 0.03%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 185959). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV000165474	SCV000685633	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 165 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and kidney renal clear cell carcinoma (PMID: 25186627, 26689913, 33471991). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 breast cancer cases and 11/53461 controls (PMID: 33471991). This variant has also been identified in 12/281892 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155097	SCV000697698	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.493G>A (p.Ala165Thr) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250516 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MUTYH causing Hereditary Breast And Ovarian Cancer Syndrome (0.0056), allowing no conclusion about variant significance. The variant, c.493G>A, has been reported in the literature in individuals with a personal- or family history of Breast and/or Ovarian Cancer, and other tumor phenotypes (Tsaousis_2019, Chen_2020). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 11/53461 controls (Dorling_2021, reported through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000228243	SCV000792228	uncertain significance	Familial adenomatous polyposis 2	2017-06-13	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000165474	SCV000822074	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000590519	SCV001875080	uncertain significance	not provided	2021-08-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with kidney or breast cancer (Lu 2015, Tung 2015, Yehia 2018); This variant is associated with the following publications: (PMID: 31159747, 29684080, 28706299, 25186627, 26689913)
Sema4, Sema4	RCV000165474	SCV002532294	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000165474	SCV004014955	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539552	SCV004783022	uncertain significance	MUTYH-related disorder	2024-01-02	criteria provided, single submitter	clinical testing	The MUTYH c.493G>A variant is predicted to result in the amino acid substitution p.Ala165Thr. This variant has been reported in individuals with breast cancer, an individual with renal clear cell carcinoma, an individual with colon cancer, and an individual undergoing hereditary cancer genetic testing (Supplement, Tung et al. 2015. PubMed ID: 25186627; Supplementary Data 12, Lu et al. 2015. PubMed ID: 26689913; Table S1, referred to as p.A162T, Raskin et al. 2017. PubMed ID: 29212164; Table S2, Wang et al. 2019. PubMed ID: 30982232); Table S5, Tsaousis et al, 2019. PubMed ID: 31159747). This variant is reported in 0.035% of alleles in individuals of East Asian descent in gnomAD. It is interpreted as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185959/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000228243	SCV004839716	uncertain significance	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 165 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and kidney renal clear cell carcinoma (PMID: 25186627, 26689913, 33471991). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 breast cancer cases and 11/53461 controls (PMID: 33471991). This variant has also been identified in 12/281892 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	RCV000228243	SCV005056031	uncertain significance	Familial adenomatous polyposis 2	2024-03-19	criteria provided, single submitter	clinical testing