Submissions for variant NM_000179.3(MSH6):c.3882del (p.Pro1295fs)

dbSNP: rs876658817

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214257	SCV000274551	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	The c.3882delT pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3882, causing a translational frameshift with a predicted alternate stop codon (p.P1295Lfs*32). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 66 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000480622	SCV000566847	pathogenic	not provided	2019-08-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with Lynch syndrome-related cancers (Roberts 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29345684, 31822864)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823682	SCV000964550	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro1295Leufs*32) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 28514183). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 230870). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000214257	SCV001350123	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193699	SCV001362732	pathogenic	Hereditary nonpolyposis colon cancer	2019-02-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3882delT (p.Pro1295LeufsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.3938_3941dupTTCA, p.Gln1314fsX6; c.3984_3987dupGTCA, p.Leu1330fsX12; c.3991C>T, p.Arg1331X). The variant was absent in 245664 control chromosomes (gnomAD). c.3882delT has been reported in the literature in an individual affected with endometrial cancer (Roberts_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003454621	SCV004185848	pathogenic	Lynch syndrome 5	2023-08-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV004804882	SCV005425000	pathogenic	Lynch syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000480622	SCV005877699	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.3882del; p.Pro1295fs variant (rs876658817, ClinVar Variation ID: 230870) has been described in individuals with Lynch syndrome (Arnold 2020, Espenschied 2017, Roberts 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide; while this may not lead to nonsense-mediated decay, it is expected to create a truncated MSH6 protein that would include a sequence of 31 amino acid residues not usually present. This variant is located in the C-terminus of the MSH6 protein, and downstream truncating variants have been reported in individuals with Lynch syndrome (Goodfellow 2003, Jori 2015, Steinke 2008). Based on available information, p.Pro1295fs is considered pathogenic. REFERENCES Arnold AM et al. Targeted deep-intronic sequencing in a cohort of unexplained cases of suspected Lynch syndrome. Eur J Hum Genet. 2020 May;28(5):597-608. PMID: 31822864. Espenschied C et al. Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. J Clin Oncol. 2017 Aug 1;35(22):2568-2575. PMID: 28514183. Goodfellow P et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. PMID: 12732731. Jori B et al. Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients. Oncotarget. 2015 Dec 1;6(38):41108-22. PMID: 26517685. Roberts M et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med. 2018 Oct;20(10):1167-1174. PMID: 29345684. Steinke V et al. No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients. Eur J Hum Genet. 2008 May;16(5):587-92. PMID: 18301448.