Submissions for variant NM_000179.3(MSH6):c.1932G>C (p.Arg644Ser)

gnomAD frequency: 0.00037  dbSNP: rs34938432

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166227	SCV000217006	likely benign	Hereditary cancer-predisposing syndrome	2019-11-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524127	SCV000254286	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001703971	SCV000279099	likely benign	not provided	2021-03-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23621914, 22290698, 19593635, 25503501, 25980754, 21153778, 26437257, 15872200, 28874130, 26333163, 28767289, 26689913)
Counsyl	RCV000409155	SCV000488252	uncertain significance	Lynch syndrome 5	2016-02-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166227	SCV000910867	likely benign	Hereditary cancer-predisposing syndrome	2015-11-10	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000074697	SCV000914309	uncertain significance	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219792	SCV000917765	likely benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1932G>C (p.Arg644Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain 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 7.2e-05 in 251166 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1932G>C has been reported in the literature in individuals affected with pancreatic cancer, Lynch syndrome undergoing multigene panel testing (example, Shindo_2017, Rossi_2017, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000409155	SCV001135813	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166227	SCV002535682	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	curation
Johns Hopkins Genomics, Johns Hopkins University	RCV000409155	SCV002570277	likely benign	Lynch syndrome 5	2022-03-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409155	SCV004019028	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered 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]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703971	SCV004221163	likely benign	not provided	2023-02-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355116	SCV001549904	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg644Ser variant was identified in 6 of 5432 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome, breast and pancreatic cancer (Yurgelun 2015, Hampel 2005, Carneiro da Silva 2015, Shindo 2017, Maxwell 2015). The variant was identified in dbSNP (rs34938432) as “with likely benign, uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Counsyl, InSiGHT and 2 other submitters and likely benign by Invitae, GeneDx, Color and 1 other submitter). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 28 of 282,560 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 27 of 24,952 chromosomes (freq: 0.001), Latino in 1 of 35,428 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other and South Asian populations. The p.Arg644 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004537274	SCV004745781	uncertain significance	MSH6-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The MSH6 c.1932G>C variant is predicted to result in the amino acid substitution p.Arg644Ser. This variant was reported in individuals with pancreatic ductal adenocarcinoma, breast cancer, or Lynch syndrome (see for example - Table S1, Maxwell et al. 2015. PubMed ID: 25503501; Shindo et al. 2017. PubMed ID: 28767289; Rossi et al. 2017. PubMed ID: 28874130; Table S3, Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/89233/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.