Submissions for variant NM_000179.3(MSH6):c.242C>T (p.Ala81Val)

gnomAD frequency: 0.00004  dbSNP: rs587779924

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588221	SCV000149300	uncertain significance	not provided	2023-09-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian cancer or MSI stable colon cancer (Pal et al., 2012; Hampel et al., 2018); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23047549, 31391288, 23621914, 29596542, 27882345, 25085752)
Ambry Genetics	RCV000115391	SCV000214975	likely benign	Hereditary cancer-predisposing syndrome	2018-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000412014	SCV000487971	uncertain significance	Lynch syndrome 5	2015-12-07	criteria provided, single submitter	clinical testing
Invitae	RCV000477204	SCV000551136	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588221	SCV000695810	uncertain significance	not provided	2016-07-25	criteria provided, single submitter	clinical testing	Variant summary: The c.242C>T (p.Ala81Val) in MSH6 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain. The variant is absent from control dataset of ExAC. This variant has been reported in affected individual developed OvC, but is cited as VUS/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000115391	SCV000910869	benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115391	SCV002535739	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000412014	SCV004018985	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	RCV003467040	SCV004195587	uncertain significance	Endometrial carcinoma	2023-08-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588221	SCV004221177	uncertain significance	not provided	2023-09-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with lung cancer (PMID: 27882345 (2016)) and ovarian cancer (PMID: 23047549 (2012)). It was also identified in cutaneous sarcomatoid carcinoma (PMID: 32540221 (2020)) and a tumor of the colon (PMID: 29596542 (2018)). The frequency of this variant in the general population, 0.000074 (5/67954 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.