Submissions for variant NM_000251.3(MSH2):c.2260A>G (p.Thr754Ala)

dbSNP: rs757268664

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196465	SCV000254403	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000560982	SCV000662296	likely benign	Hereditary cancer-predisposing syndrome	2023-03-30	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	RCV000560982	SCV000685028	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 754 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal (PMID: 29212164), pancreatic (PMID: 26692440, 32980694), bladder (PMID: 34213665), and breast cancer (PMID: 33471991), as well as in a large amount of healthy controls in a large pancreatic case-control study (PMID: 32980694). This variant has also been identified in 3/251408 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589091	SCV000696243	uncertain significance	not provided	2016-06-14	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.2260A>G (p.Thr754Ala) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome for this variant, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121344 (1/60672), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH2 variant of 1/1759 (0.0005683). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, a clinical laboratory does cite the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Illumina Laboratory Services, Illumina	RCV001140258	SCV001300497	uncertain significance	Lynch syndrome 1	2017-05-01	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000589091	SCV001747254	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000560982	SCV002534461	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002500622	SCV002775285	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-02-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997019	SCV004825803	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 754 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal (PMID: 29212164), pancreatic (PMID: 26692440, 32980694), bladder (PMID: 34213665), and breast cancer (PMID: 33471991), as well as in a large amount of healthy controls in a large pancreatic case-control study (PMID: 32980694). This variant has also been identified in 3/251408 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.