Submissions for variant NM_000179.3(MSH6):c.1109T>C (p.Leu370Ser)

dbSNP: rs587779204

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162441	SCV000212790	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	clinical testing	The p.L370S pathogenic mutation (also known as c.1109T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1109. The leucine at codon 370 is replaced by serine, an amino acid with dissimilar properties. This variant has been found to co-segregate with disease in HNPCC/Lynch syndrome families (Ambry internal data; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This variant was detected in 1/173 unselected Spanish women with endometrial cancer; tumor studies for this individual showed microsatellite stability (MSS) with loss of MSH6 protein expression, but intact MSH2 protein expression (Egoavil C et al. PLoS One. 2013 Nov 7;8(11):e79737). This alteration was also detected in a 53-year-old woman whose endometrial cancer showed low microsatellite instability (MSI-L) with normal protein expression for all the mismatch repair proteins; family history was noncontributory (Batte BA et al. Gynecol Oncol. 2014 Aug;134(2):319-25). In addition, this variant has been identified in numerous individuals whose HNPCC/Lynch syndrome-associated tumors demonstrated isolated loss of MSH6 staining on immunohistochemistry and/or had family histories that met Amsterdam II criteria (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000524101	SCV000261301	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 370 of the MSH6 protein (p.Leu370Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with endometrial cancer and/or colorectal cancer (PMID: 24244552, 24933100, 27978560; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89172). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000518839	SCV000568050	likely pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Egoavil et al., 2013; Batte et al., 2014; Pearlman et al., 2017; Ranola et al., 2018; Chen et al., 2020; Hampel et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24244552, 24933100, 26333163, 23621914, 27978560, 30019097, 33393477, 30695780, 32652087, 32719484, 35366121, 17531815, 21120944, 31391288, 34994648)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074633	SCV000579493	pathogenic	Lynch syndrome	2016-05-17	criteria provided, single submitter	clinical testing	Co-segregation likelihood ratio >250, shared with 3th cousin with loss of MSH6 and others with Lynch cancers in large pedigree, likelihood ration for cosegregation >250
Color Diagnostics, LLC DBA Color Health	RCV000162441	SCV000685164	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 370 of the MSH6 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 reported for this variant. This variant has been observed in individuals affected with Lynch syndrome (PMID: 32652087, 33393477), with endometrial cancer and/or colorectal cancer (PMID: 24933100, 24244552, 28765196, 30019097), or unspecified cancers (PMID: 28765196). Moreover, it has been observed to segregate with Lynch syndrome related cancers in one family (PMID: 27978560). In addition, a multifactorial likelihood model using in silico data have suggested this variant have a high probability of being deleterious (PMID: 23621914). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201190	SCV001372259	pathogenic	Hereditary nonpolyposis colon cancer	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1109T>C (p.Leu370Ser) 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. The variant was absent in 250994 control chromosomes (gnomAD). c.1109T>C has been reported in the literature in multiple individuals affected with Lynch Syndrome and endometrial cancer (example, Egoavil_2013, Pearlman_2017, Chen_2020, Li_2020, Hampel_2021). Most of the reported patients were noted with loss of MSH6 expression in tumors by IHC analysis, although one patient was reported with intact MSH6 (Chen_2020). Furthermore, one of these studies reported co-segregation of the variant with disease among two first and second generation relatives within the family (Pearlman_2017). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic (n=1) and as likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074633	SCV001653079	likely pathogenic	Lynch syndrome	2020-02-10	criteria provided, single submitter	clinical testing	The p.Leu370Ser variant in MSH6 has been identified in at least 14 individuals with Lynch syndrome associated cancers and segregated with disease in 4 affected relatives from 2 families (Egoavil 2013, Batte 2014, Pearlman 2017, GeneDx pers. comm., Ambry pers. comm.). In addition, tumors sampled from at least 10 individuals lacked MSH6 expression and/or showed high microsatellite instability, while at least one tumor showed normal MSH6 expression and/or low microsatellite instability. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID #89172) and was absent from large population studies. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4, PM2, PP1.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202023	SCV002046204	likely pathogenic	not specified	2020-11-05	criteria provided, single submitter	clinical testing	The variant has been reported in multiple individuals suspected of having Lynch syndrome in the published literature (PMID: 32652087 (2020), 30019097 (2019), 27978560 (2016), 24933100 (2014), 24244552 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This varaint is located in a potentially critical protein domain. Based on the available information, we predict that the variant is likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000518839	SCV002522522	likely pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PS4_moderate
Revvity Omics, Revvity	RCV000518839	SCV003833154	likely pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450922	SCV004185558	likely pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Laboratory for Genotyping Development, RIKEN	RCV003162468	SCV002758539	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research