Submissions for variant NM_001048174.2(MUTYH):c.953C>T (p.Ser318Leu)

gnomAD frequency: 0.00003  dbSNP: rs587778538

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123137	SCV000166439	uncertain significance	Familial adenomatous polyposis 2	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 346 of the MUTYH protein (p.Ser346Leu). This variant is present in population databases (rs587778538, gnomAD 0.04%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25186627, 25980754, 30982232). ClinVar contains an entry for this variant (Variation ID: 134862). 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.
Ambry Genetics	RCV000216934	SCV000275946	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The p.S346L variant (also known as c.1037C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1037. The serine at codon 346 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This alteration was also identified in a cohort of 481 Chinese breast cancer patients with family history of breast/ovarian cancer (Wang J et al. Cancer Med, 2019 05;8:2074-2084). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000123137	SCV000487349	uncertain significance	Familial adenomatous polyposis 2	2016-04-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216934	SCV001346480	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 346 of the MUTYH protein. 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 an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in two individual affected with breast and/or ovarian cancer (PMID: 25186627). This variant has been identified in 14/273222 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	RCV000121595	SCV001370687	uncertain significance	not specified	2020-05-26	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1037C>T (p.Ser346Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 241834 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (5.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.1037C>T has been reported in the literature in sequencing studies of individuals affected with and/or undergoing testing for breast cancer, colorectal cancer (example, Tung_2015, Yurgelun_2015, Wang_2019). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001582593	SCV001818942	uncertain significance	not provided	2024-04-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Ser343Leu (c.1028C>T); This variant is associated with the following publications: (PMID: 24728327, 30982232, 36243179, 16879101, 20816984, 25980754, 25186627)
Sema4, Sema4	RCV000216934	SCV002532198	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	curation
Baylor Genetics	RCV000123137	SCV004198848	uncertain significance	Familial adenomatous polyposis 2	2024-03-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123137	SCV004835070	uncertain significance	Familial adenomatous polyposis 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 346 of the MUTYH protein. 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 an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in two individual affected with breast and/or ovarian cancer (PMID: 25186627). This variant has been identified in 14/273222 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	RCV000121595	SCV000085791	not provided	not specified	2013-09-19	no assertion provided	reference population