Submissions for variant NM_000251.3(MSH2):c.932del (p.Asn311fs)

dbSNP: rs587779979

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115548	SCV000149457	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in the published literature (Susswein et al., 2016; Roberts et al., 2018); This variant is associated with the following publications: (PMID: 26681312, 29345684, 30787465)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232943	SCV000284196	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-07-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn311Thrfs*20) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colon polyps (PMID: 26681312). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 127655). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491121	SCV000580385	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-02	criteria provided, single submitter	clinical testing	The c.932delA pathogenic mutation, located in coding exon 5 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 932, causing a translational frameshift with a predicted alternate stop codon (p.N311Tfs*20). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115548	SCV000889445	pathogenic	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491121	SCV001354534	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 5 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193288	SCV001362023	pathogenic	Hereditary nonpolyposis colon cancer	2019-06-13	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.932delA (p.Asn311ThrfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 230146 control chromosomes (gnomAD). c.932delA has been reported in the literature in an individual affected with colon polyps (Susswein_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003453043	SCV004188155	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003453043	SCV004196946	pathogenic	Lynch syndrome 1	2020-10-13	criteria provided, single submitter	clinical testing