Submissions for variant NM_000535.7(PMS2):c.714C>A (p.Ser238Arg)

gnomAD frequency: 0.00010  dbSNP: rs151251082

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079111	SCV000110980	uncertain significance	not provided	2013-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129639	SCV000184434	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	The p.S238R variant (also known as c.714C>A), located in coding exon 7 of the PMS2 gene, results from a C to A substitution at nucleotide position 714. The serine at codon 238 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000229467	SCV000285151	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 238 of the PMS2 protein (p.Ser238Arg). This variant is present in population databases (rs151251082, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 93236). 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.
Counsyl	RCV000662416	SCV000784852	uncertain significance	Lynch syndrome 4	2017-01-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000708994	SCV000838191	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129639	SCV000911640	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 238 of the PMS2 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). Functional studies have shown that this variant caused increased protein expression and had no significant impact on mismatch repair or ATPase activity compared to wild type protein (PMID: 35189042). This variant has been reported in an individual affected with breast cancer (DOI: 10.1101/2021.04.15.21255554v2). This variant has been identified in 9/258576 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000079111	SCV001134611	uncertain significance	not provided	2018-09-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000079111	SCV001782267	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with breast cancer (Guindalini et al., 2022); Published functional studies suggest no damaging effect: no significant impact on mismatch repair (MMR) activity (D'Arcy et al., 2022); This variant is associated with the following publications: (PMID: 11574484, 35264596, 35189042)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000662416	SCV002012381	uncertain significance	Lynch syndrome 4	2021-09-01	criteria provided, single submitter	clinical testing	The PMS2 c.714C>A (p.Ser238Arg) missense change has a maximum subpopulation frequency of 0.031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6037046-G-T). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Centogene AG - the Rare Disease Company	RCV000662416	SCV002059436	uncertain significance	Lynch syndrome 4	2018-09-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662416	SCV004019890	uncertain significance	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662416	SCV004205339	uncertain significance	Lynch syndrome 4	2023-10-30	criteria provided, single submitter	clinical testing