Submissions for variant NM_000251.3(MSH2):c.80C>T (p.Pro27Leu)

gnomAD frequency: 0.00002  dbSNP: rs750746034

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164692	SCV000215359	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.
Invitae	RCV000228123	SCV000284189	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000235224	SCV000292613	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in an individual with early onset mismatch repair (MMR) deficient colon cancer; however, this individual was also found to harbor a truncating variant in MLH1 which could explain the observed MMR deficiency (Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 22949387, 29596542, 18822302, 21120944, 27978560)
Counsyl	RCV000412025	SCV000489554	uncertain significance	Lynch syndrome 1	2016-10-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164692	SCV000685130	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 27 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 an individual affected with colorectal cancer who also carried a pathogenic MLH1 variant that could explain the observed phenotype (PMID: 27978560). This variant has also been reported in an individual affected with thyroid and/or breast cancer (PMID: 32443704). This variant has been identified in 8/218450 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.
Mendelics	RCV003993847	SCV000837812	likely benign	Hereditary nonpolyposis colon cancer	2024-04-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235224	SCV001134375	uncertain significance	not provided	2018-08-30	criteria provided, single submitter	clinical testing
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001374485	SCV001438637	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-08-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000164692	SCV002526747	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226226	SCV003922587	uncertain significance	not specified	2023-03-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.80C>T (p.Pro27Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 218450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.80C>T has been reported in the literature in individuals affected with Lynch Syndrome or different cancers (Chen_2020, Felicio_2021, Muskens_2020, Ollodart_2021, Pearlman_2021, Pinhero_2020, Solmaz_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with another pathogenic variant has been reported (MLH1 c.2252_2253del, p.Lys751fs), providing supporting evidence for a benign role (Chen_2020). At least one publication reports experimental evidence evaluating an impact on the mutation rate of the orthologous variant in yeast cells, finding no significant impact (Ollodart_2021). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=8) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000412025	SCV004018255	likely benign	Lynch syndrome 1	2023-09-19	criteria provided, single submitter	clinical testing	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: 27363726].
Baylor Genetics	RCV000412025	SCV004196259	uncertain significance	Lynch syndrome 1	2023-09-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995359	SCV004826338	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 27 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer with a pathogenic MLH1 covariant that likely explains the disease (PMID: 27978560). This variant has been identified in 8/218450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.