Submissions for variant NM_000535.7(PMS2):c.1199A>C (p.Gln400Pro)

gnomAD frequency: 0.00045  dbSNP: rs148069478

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131944	SCV000187000	likely benign	Hereditary cancer-predisposing syndrome	2020-01-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084751	SCV000252712	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657027	SCV000566765	uncertain significance	not provided	2022-01-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with early-onset colorectal cancer whose tumor demonstrated normal expression of mismatch repair proteins on immunohistochemistry (Pearlman 2017); This variant is associated with the following publications: (PMID: 22675565, 29596542, 27978560)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657027	SCV000601810	likely benign	not provided	2020-04-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131944	SCV000902969	likely benign	Hereditary cancer-predisposing syndrome	2015-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483430	SCV001338555	likely benign	not specified	2023-11-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131944	SCV002529766	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-06	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003422029	SCV004116775	uncertain significance	PMS2-related disorder	2023-04-07	criteria provided, single submitter	clinical testing	The PMS2 c.1199A>C variant is predicted to result in the amino acid substitution p.Gln400Pro. This variant has been reported in an individual with with early-onset colorectal cancer with normal mismatch repair protein expression in the tumor on imunohistochemisty (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). It has also been reported in an individual with T-cell acute lymphoblastic leukemia (Table S3, Atak et al. 2012. PubMed ID: 22675565). In the gnomAD public population database this variant has been reported in up to 0.1 % of alleles in an African subpopulation (http://gnomad.broadinstitute.org/variant/7-6027197-T-G). However, this variant occurs in a highly paralogous region and allele frequency data should be interpreted with caution. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/142625/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.