Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_000251.3(MSH2):c.287G>A(p.Arg96His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,611,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96C) has been classified as Uncertain significance.
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Variant 2-47408476-G-A is Benign according to our data. Variant chr2-47408476-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 91053.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47408476-G-A is described in Lovd as [Likely_benign].
Likely benign, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Mar 22, 2023
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]. -
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Feb 23, 2017
- -
Likely benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Nov 25, 2015
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Feb 01, 2019
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. -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 30, 2020
Variant summary: MSH2 c.287G>A (p.Arg96His) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.287G>A has been reported in the literature together with an MSH2 frameshift variant in a family affected with Lynch Syndrome, authors noted that the variant of interest did not segregate with the disease (Wijnen_1995). In addition, a co-occurrence with a (likely) pathogenic variant has also been reported (RAD51C c.1026+5_1026+7delGTA; in an LCA internal sample), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no effect on MMR activity for this variant (Martinez_2010, Houlleberghs_2016). Six submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar without evidence for independent evaluation, and all of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Lynch syndrome Benign:1
Likely benign, reviewed by expert panel
research
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Sep 05, 2013
Multifactorial likelihood analysis posterior probability 0.001-0.049 -
not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jun 01, 2021
This variant is associated with the following publications: (PMID: 9311737, 18547406, 12547705, 12414824, 15340264, 22949387, 17074586, 7726159, 20176959, 22045683, 27266541) -