Submissions for variant NM_000179.3(MSH6):c.3625C>T (p.Leu1209=)

gnomAD frequency: 0.00001  dbSNP: rs753675331

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458242	SCV000561518	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491628	SCV000580186	likely benign	Hereditary cancer-predisposing syndrome	2016-03-15	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.
Color Diagnostics, LLC DBA Color Health	RCV000491628	SCV000685422	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000602317	SCV000729049	likely benign	not specified	2017-11-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000602317	SCV001448565	likely benign	not specified	2020-11-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002171	SCV004835106	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355327	SCV001550189	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Leu1209= variant was not identified in the literature, nor was it identified in the GeneInsight-COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs753675331) as "With Likely benign allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color Genomics, and GeneDx). The variant was identified in control databases in 6 of 246222 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33570 chromosomes (freq: 0.00003) and East Asian in 5 of 17248 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Leu1209= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.