Submissions for variant NM_000179.3(MSH6):c.1867C>G (p.Pro623Ala)

gnomAD frequency: 0.00033  dbSNP: rs3136334

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128867	SCV000172724	likely benign	Hereditary cancer-predisposing syndrome	2018-07-03	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.
Invitae	RCV001082588	SCV000218546	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000034494	SCV000279098	likely benign	not provided	2020-10-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26333163, 24728327, 22703879, 22949387, 17417778, 22290698, 23621914, 28531214, 21153778, 26580448, 24393486)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000074692	SCV000296879	uncertain significance	Lynch syndrome	2015-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034494	SCV000601519	likely benign	not provided	2023-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121577	SCV000695798	likely benign	not specified	2022-10-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1867C>G (p.Pro623Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function, and other published computational predictions suggest a neutral impact (e.g. Ali_2012, Terui_2013, Niroula_2015). The variant allele was found at a frequency of 9.2e-05 in 250462 control chromosomes, predominantly at a frequency of 0.0014 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 10-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.1867C>G has been reported in the literature in individuals affected with Cancer with limited clinical information and without evidence of causality (Zhang_2015, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, showing no damaging effect of this variant in an oligonucleotide-directed mutagenesis screening assay measuring 6TG resistance in MMR-deficient cells (Houlleberghs_2017). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=6; uncertain significance, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000662448	SCV000784919	uncertain significance	Lynch syndrome 5	2017-02-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128867	SCV000902977	likely benign	Hereditary cancer-predisposing syndrome	2016-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000662448	SCV001481468	uncertain significance	Lynch syndrome 5	2020-10-15	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000128867	SCV002535669	likely benign	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004534719	SCV004719604	likely benign	MSH6-related disorder	2023-07-07	criteria provided, single submitter	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).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034494	SCV000043357	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121577	SCV000085773	not provided	not specified	2013-09-19	no assertion provided	reference population