Submissions for variant NM_000535.7(PMS2):c.355G>A (p.Asp119Asn)

gnomAD frequency: 0.00003  dbSNP: rs587781913

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000552145	SCV000625646	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 119 of the PMS2 protein (p.Asp119Asn). This variant is present in population databases (rs587781913, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 455716). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589176	SCV000697365	uncertain significance	not specified	2019-09-20	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.355G>A (p.Asp119Asn) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, the variant is located close to a canonical splice site and therefore could affect mRNA splicing: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251140 control chromosomes (gnomAD). This observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.355G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000776344	SCV000911704	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 119 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 2/282534 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.
Ambry Genetics	RCV000776344	SCV001182112	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.D119N variant (also known as c.355G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 355. The aspartic acid at codon 119 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001591190	SCV001824999	uncertain significance	not provided	2019-10-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150261	SCV003838397	uncertain significance	Breast and/or ovarian cancer	2022-05-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470719	SCV004205439	uncertain significance	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905322	SCV004721602	uncertain significance	PMS2-related condition	2023-10-26	criteria provided, single submitter	clinical testing	The PMS2 c.355G>A variant is predicted to result in the amino acid substitution p.Asp119Asn. This variant was reported in one control but not in affected individuals in a large breast cancer case-control study (described as chr7_6042266_C_T in Supplementary Data, Breast Cancer Association et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6042266-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/455716/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.