Submissions for variant NM_000179.3(MSH6):c.3244C>T (p.Pro1082Ser)

gnomAD frequency: 0.00002  dbSNP: rs186240214

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129766	SCV000184575	likely benign	Hereditary cancer-predisposing syndrome	2023-10-19	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.
GeneDx	RCV000586138	SCV000211316	uncertain significance	not provided	2018-04-10	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3244C>T at the cDNA level, p.Pro1082Ser (P1082S) at the protein level, and results in the change of a Proline to a Serine (CCG>TCG). This variant was observed in a patient with sporadic colorectal cancer whose tumor was microsatellite stable, demonstrated microsatellite stability, loss of MLH1and PMS2 expression on immunohistochemistry, and was positive for MLH1 promoter hypermethylation (Terui 2013). MSH6 Pro1082Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Pro1082Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000409325	SCV000487794	uncertain significance	Lynch syndrome 5	2015-11-24	criteria provided, single submitter	clinical testing
Invitae	RCV000464994	SCV000551272	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515187	SCV000611404	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129766	SCV000685370	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 1082 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 three individuals affected with colorectal cancer (PMID: 24100870, 33294277), in an individual affected with urothelial carcinoma (PMID: 33588785), and in at least six individuals suspected of having hereditary breast and ovarian cancer (PMID: 30982232, 31742824). In the colorectal cancer cases, one individual had a pathogenic MLH1 covariant and in a second case the methylation of MLH1 was detected along with the loss of MLH1 and PMS2 proteins by immunohistochemistry (PMID: 24100870, 33294277). This variant also has been detected in a pancreatic cancer case-control study in which it was found in five unaffected control individuals and absent in affected individuals (PMID: 32980694), as well as a breast cancer case-control study where it was found in 11 affected individuals and 12 unaffected control individuals (PMID: 33471991). This variant has been identified in 13/282780 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	RCV001175358	SCV000695849	likely benign	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3244C>T (p.Pro1082Ser) results in a non-conservative amino acid change located in the core domain (IPR007696) of 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 4.8e-05 in 251392 control chromosomes, exclusively reported within the East Asian subpopulation, at a frequency of 0.00065 (gnomAD). The observed variant frequency within East Asian control individuals is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.3244C>T, has been reported in the literature in a Japanese colorectal cancer patient, however without strong evidence of causality (Terui_2013). The variant was also found in multiple Chinese individuals with personal- or family history of breast- or ovarian cancer (Wang_2019, Shao_2019). In one of these patients however, a co-occurring pathogenic variant has been reported (BRCA1 c.5521delA (p.Ser1841fs); Wang_2019) that could explain the phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153418	SCV003843490	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409325	SCV004019047	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003467119	SCV004197568	uncertain significance	Endometrial carcinoma	2023-10-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997523	SCV004835017	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 1082 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 three individuals affected with colorectal cancer (PMID: 24100870, 33294277), in an individual affected with urothelial carcinoma (PMID: 33588785), and in at least six individuals suspected of having hereditary breast and ovarian cancer (PMID: 30982232, 31742824). In the colorectal cancer cases, one individual had a pathogenic MLH1 covariant and in a second case the methylation of MLH1 was detected along with the loss of MLH1 and PMS2 proteins by immunohistochemistry (PMID: 24100870, 33294277). This variant also has been detected in a pancreatic cancer case-control study in which it was found in five unaffected control individuals and absent in affected individuals (PMID: 32980694), as well as a breast cancer case-control study where it was found in 11 affected individuals and 12 unaffected control individuals (PMID: 33471991). This variant has been identified in 13/282780 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.