Submissions for variant NM_000179.3(MSH6):c.432C>T (p.Ser144=)

dbSNP: rs1046304919

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082030	SCV000561530	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491454	SCV000580243	likely benign	Hereditary cancer-predisposing syndrome	2016-05-13	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.
GeneDx	RCV000521132	SCV000618507	uncertain significance	not provided	2017-05-31	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.432C>T at the DNA level. Although this variant is silent at the coding level, preserving a Serine at codon 144, it is predicted to cause abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 c.432C>T was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a cytosine (C) at base 432, is not conserved. Based on currently available information, it is unclear whether MSH6 c.432C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000491454	SCV001348045	likely benign	Hereditary cancer-predisposing syndrome	2019-06-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000521132	SCV004011160	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
All of Us Research Program, National Institutes of Health	RCV004002173	SCV004829220	likely benign	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355486	SCV001550388	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Ser144= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, UMD-LSDB, Zhejiang University, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs1046304919) as "With Likely benign allele", and in ClinVar (classified as likely benign by Invite and Ambry Genetics; as uncertain significance by GeneDx). The variant was identified in control databases in 1 of 246240 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the European population in 1 of 111692 chromosomes (freq: 0.00001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ser144= 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. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.