Submissions for variant NM_000179.3(MSH6):c.4000C>T (p.Arg1334Trp)

gnomAD frequency: 0.00006  dbSNP: rs773763465

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163638	SCV000214206	likely benign	Hereditary cancer-predisposing syndrome	2023-10-12	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.
Invitae	RCV000198598	SCV000254324	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1334 of the MSH6 protein (p.Arg1334Trp). This variant is present in population databases (rs773763465, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer, and/or pancreatic cancer (PMID: 25559809, 29360161, 35449176). ClinVar contains an entry for this variant (Variation ID: 184389). 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. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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.
GeneDx	RCV000657088	SCV000279624	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal and family history of colon cancer as well as individuals with a personal history of breast cancer, one of whom also had pancreatic cancer (Chubb et al., 2015; Dudley et al., 2018; Hu et al., 2022; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25559809, 25275298, 29360161, 31391288, 23415222, 33471991, 35449176, 21120944, 12019211, 17531815, 25370038)
Counsyl	RCV000409323	SCV000488106	uncertain significance	Lynch syndrome 5	2015-12-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657088	SCV000601597	uncertain significance	not provided	2019-10-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163638	SCV000685474	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. 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. This variant has been reported in an individual affected by early-onset, familial colorectal cancer (PMID: 25559809). This variant has been identified in 11/275890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.4001G>A (p.Arg1334Gln), is considered to be disease-causing (ClinVar variation ID: 89506), suggesting that this position is important for the protein function. 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	RCV001706075	SCV001821390	uncertain significance	not specified	2021-08-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4000C>T (p.Arg1334Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.7e-05 in 244568 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4000C>T has been reported in the literature as somatic occurrence in individuals affected with chronic lymphocytic leukemia, HNSCC, polyposis and endometrial cancer (Landau_2013, Martin_2014, Elsayed_2015) and as germline occurrence in individuals affected with cancer including colorectal, pancreatic and breast cancer (Chubb_2015, Dudley_2018, Li_2020, Dorling_2021), but it was also reported in controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000409323	SCV004018890	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	RCV003462121	SCV004197638	uncertain significance	Endometrial carcinoma	2023-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995266	SCV004835193	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. 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. This variant has been reported in an individual affected by early-onset, familial colorectal cancer (PMID: 25559809). This variant has been identified in 11/275890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.4001G>A (p.Arg1334Gln), is considered to be disease-causing (ClinVar variation ID: 89506), suggesting that this position is important for the protein function. 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.