Submissions for variant NM_000251.3(MSH2):c.992A>G (p.Asn331Ser)

gnomAD frequency: 0.00001  dbSNP: rs779673318

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572560	SCV000664856	likely benign	Hereditary cancer-predisposing syndrome	2022-05-28	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.
Invitae	RCV000629913	SCV000750869	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 331 of the MSH2 protein (p.Asn331Ser). This variant is present in population databases (rs779673318, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian and gastric cancer (PMID: 25133505). ClinVar contains an entry for this variant (Variation ID: 480911). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics	RCV000708829	SCV000837824	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000572560	SCV001355779	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 331 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This missense protein has been reported in an individual affected with gastric and ovarian cancer, however, the cDNA change provided, c.992A>C, encodes a different protein change, p.Asn331Thr (PMID: 25133505). This variant has been identified in 2/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002483525	SCV002789007	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-04-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320694	SCV004025237	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing