Submissions for variant NM_000535.7(PMS2):c.1952A>G (p.Lys651Arg)

gnomAD frequency: 0.00001  dbSNP: rs267608167

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234457	SCV000285095	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 651 of the PMS2 protein (p.Lys651Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 237896). 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 not expected to disrupt PMS2 protein function with a negative 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.
Ambry Genetics	RCV000569086	SCV000663447	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	The p.K651R variant (also known as c.1952A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1952. The lysine at codon 651 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other 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.
Counsyl	RCV000662633	SCV000785317	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569086	SCV000903233	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 651 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 3/250440 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.
GeneDx	RCV001762519	SCV002008438	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17016615, 33004033, 32368696, 11292842)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798732	SCV002042792	uncertain significance	Breast and/or ovarian cancer	2021-09-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662633	SCV004019836	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	RCV000662633	SCV004205403	uncertain significance	Lynch syndrome 4	2023-10-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998790	SCV004844112	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 651 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 3/250440 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354896	SCV001549617	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Lys651Arg variant was identified in 5 of 40 proband chromosomes (frequency: 0.125) from individuals or families with breast cancer (Balogh 2006). The variant was also identified in dbSNP (ID: rs267608167) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Invitae, Ambry Genetics, and Counsyl, and as likely benign by Color). The variant was identified in control databases in 4 of 276286 chromosomes at a frequency of 0.000014 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 2 of 126486 chromosomes (freq: 0.000016), Ashkenazi Jewish in 1 of 10082 chromosomes (freq: 0.000099), and European (Finnish) in 1 of 25788 chromosomes (freq: 0.000039), while the variant was not observed in the African, Other, Latino, East Asian, and South Asian populations. The p.Lys651 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.