Submissions for variant NM_000179.3(MSH6):c.4005A>C (p.Glu1335Asp)

gnomAD frequency: 0.00002  dbSNP: rs786204130

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168100	SCV000218756	benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000213342	SCV000275221	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing	The p.E1335D variant (also known as c.4005A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4005. The glutamic acid at codon 1335 is replaced by aspartic acid, an amino acid with highly similar properties. Another alteration at the same location, p.E1335A (c.4004A>C), has been reported in one family that met Amsterdam criteria and was shown to segregate with disease. The proband was diagnosed with colon cancer at age 42; however, tumor testing showed wild-type BRAF analysis, microsatellite stability, and normal IHC staining (Pérez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000213342	SCV000685483	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1335 of the MSH6 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/238052 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.
Counsyl	RCV000663216	SCV000786402	uncertain significance	Lynch syndrome 5	2018-05-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800508	SCV002046627	uncertain significance	not provided	2021-02-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213342	SCV002536313	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	curation
GeneDx	RCV001800508	SCV002757704	uncertain significance	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Absent from cases but observed in one control in a breast cancer case-control study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 17531815, 21120944, 12019211, 23523604, 29386642)
Myriad Genetics, Inc.	RCV000663216	SCV004018872	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003462256	SCV004197590	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987391	SCV004804233	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4005A>C (p.Glu1335Asp) 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 4.1e-06 in 242940 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4005A>C in individuals affected with Prostate Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 188188). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003995607	SCV004835196	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1335 of the MSH6 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/238052 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.