Submissions for variant NM_000535.7(PMS2):c.1026A>C (p.Gln342His)

dbSNP: rs561993366

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164831	SCV000215514	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.Q342H variant (also known as c.1026A>C), located in coding exon 10 of the PMS2 gene, results from an A to C substitution at nucleotide position 1026. The glutamine at codon 342 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in one individual from a cohort of patients with Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant has also been detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000206306	SCV000261318	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 342 of the PMS2 protein (p.Gln342His). This variant is present in population databases (rs561993366, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 185416). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive 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.
GeneDx	RCV000482141	SCV000566029	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and in a cohort of patients with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome without identifiable PTEN variants (PMID: 25186627, 29684080, 33471991); This variant is associated with the following publications: (PMID: 22895193, 25186627, 29684080, 11574484, 31391288, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000164831	SCV000904178	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 342 of the PMS2 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627), as well as two unaffected controls in a large breast cancer case-control study (PMID: 33471991). This variant has been identified in 2/251024 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.
Illumina Laboratory Services, Illumina	RCV001162268	SCV001324215	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317118	SCV004020714	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1026A>C (p.Gln342His) results in a non-conservative amino acid change in 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 8e-06 in 251024 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1026A>C has been reported in the literature in individuals affected with breast cancer or with clinical features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (examples: Tung_2015, Yehia_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.2057G>A, p.Gly686Asp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25186627, 29684080). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003995367	SCV004839861	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 342 of the PMS2 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627), as well as two unaffected controls in a large breast cancer case-control study (PMID: 33471991). This variant has been identified in 2/251024 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.