Submissions for variant NM_000179.3(MSH6):c.124C>T (p.Pro42Ser)

gnomAD frequency: 0.00011  dbSNP: rs34014629

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131942	SCV000186998	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	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	RCV000524105	SCV000253087	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000410444	SCV000488256	uncertain significance	Lynch syndrome 5	2016-02-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001719808	SCV000513671	likely benign	not provided	2020-11-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25980754, 21153778, 23621914, 22290698, 15872200, 22949387, 26437257, 23581296, 28874130, 19593635, 31647837)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422207	SCV000695777	likely benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.124C>T (p.Pro42Ser) results in a non-conservative amino acid change located in the PWWP domain (IPR000313) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function, and two independent tools developed and reported in the literature predict the variant to be neutral (Terui_2013, Ali_2012). The variant allele was found at a frequency of 0.00011 in 227574 control chromosomes, predominantly at a frequency of 0.0019 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 13 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.124C>T, has been reported in the literature in individuals affected with colorectal cancer or with suspected Lynch Syndrome (example, Hampel_2005, Yurgelun_2015, da Silva_2015, Rossi_ 2017). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000131942	SCV000902798	likely benign	Hereditary cancer-predisposing syndrome	2015-09-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000410444	SCV001135775	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131942	SCV002535614	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	curation
Johns Hopkins Genomics, Johns Hopkins University	RCV000410444	SCV002570276	likely benign	Lynch syndrome 5	2022-03-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149716	SCV003837636	likely benign	Breast and/or ovarian cancer	2021-07-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410444	SCV004019091	benign	Lynch syndrome 5	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered benign. 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. 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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719808	SCV004221139	likely benign	not provided	2022-10-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354476	SCV001549103	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Pro42Ser variant was identified in 3 of 3168 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch Syndrome (Hampel 2005, Yurgelun 2015, Carneiro da Silva 2015 26437257). The variant was identified in dbSNP (rs34014629) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and 2 other submitters; and as uncertain significance by InSiGHT and Counsyl). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 40 of 258,896 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 39 of 21,150 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant) and Latino in 1 of 34,080 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The p.Pro42 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	RCV004542739	SCV004765113	likely benign	MSH6-related disorder	2022-06-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).