Submissions for variant NM_000535.7(PMS2):c.106A>C (p.Ser36Arg)

gnomAD frequency: 0.00001  dbSNP: rs587781918

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130264	SCV000185108	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	The p.S36R variant (also known as c.106A>C), located in coding exon 2 of the PMS2 gene, results from an A to C substitution at nucleotide position 106. The serine at codon 36 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in higher 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	RCV000228325	SCV000285042	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-17	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 36 of the PMS2 protein (p.Ser36Arg). This variant is not present in population databases (gnomAD no frequency). 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: 141660). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 28494185). 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	RCV000484647	SCV000566579	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Dorling et al., 2021); Published functional studies demonstrate no effect on PMS2 function (Arora et al., 2017); This variant is associated with the following publications: (PMID: 25848751, 11574484, 33471991, 28494185)
Counsyl	RCV000662593	SCV000785222	uncertain significance	Lynch syndrome 4	2017-06-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130264	SCV000909682	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 36 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). A functional study reported this variant has no impact on expression, viability, or DNA damage response signaling compared to wild type PMS2 protein (PMID: 28494185). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has not been identified 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.
Sema4, Sema4	RCV000130264	SCV002529750	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662593	SCV004019816	uncertain significance	Lynch syndrome 4	2023-04-04	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	RCV000662593	SCV004205462	uncertain significance	Lynch syndrome 4	2023-09-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998049	SCV004842162	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 36 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). 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 not been identified 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.