Submissions for variant NM_000535.7(PMS2):c.611A>G (p.Asn204Ser)

gnomAD frequency: 0.00004  dbSNP: rs777903002

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220089	SCV000275861	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-06	criteria provided, single submitter	clinical testing	The p.N204S variant (also known as c.611A>G), located in coding exon 6 of the PMS2 gene, results from an A to G substitution at nucleotide position 611. The asparagine at codon 204 is replaced by serine, an amino acid with highly similar properties. This alteration was identified in 1/278 individuals from a cohort BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). This alteration was observed in the TCGA colorectal adenocarcinoma data set, which was used to represent sporadic cancer in a study of patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med, 2020 May;382:2103-2116). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000228608	SCV000285142	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 204 of the PMS2 protein (p.Asn204Ser). This variant is present in population databases (rs777903002, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 231881). 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	RCV000409096	SCV000489314	uncertain significance	Lynch syndrome 4	2016-09-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220089	SCV000906588	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 204 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 33471991). This variant has also been identified in 7/282878 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	RCV001565175	SCV001788472	uncertain significance	not provided	2020-06-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Maxwell 2015); This variant is associated with the following publications: (PMID: 25503501)
Mendelics	RCV002247656	SCV002519145	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000220089	SCV002530368	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002247656	SCV002548072	uncertain significance	not specified	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.611A>G (p.Asn204Ser) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.611A>G has been reported in the literature in an individual affected with early onset breast cancer (Maxwell_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25503501). Seven 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.
Myriad Genetics, Inc.	RCV000409096	SCV004019817	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.
PreventionGenetics, part of Exact Sciences	RCV003417789	SCV004106185	uncertain significance	PMS2-related condition	2023-09-06	criteria provided, single submitter	clinical testing	The PMS2 c.611A>G variant is predicted to result in the amino acid substitution p.Asn204Ser. This variant was reported in individuals with breast cancer; however, no additional studies were performed to help assess the pathogenicity of this variant (Table S1, Maxwell et al. 2015. PubMed ID: 25503501; supplementary dataset, Breast Cancer Association et al. 2021. PubMed ID: 33471991). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6038833-T-C) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/231881/). A different nucleotide substitution affecting the same amino acid (p.Asn204His) has been reported in a cohort of individuals with a personal or family history of breast and/or ovarian cancer (Table S1, Castéra et al. 2014. PubMed ID: 24549055). At this time, the clinical significance of the c.611A>G (p.Asn204Ser) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000409096	SCV004207847	uncertain significance	Lynch syndrome 4	2023-05-09	criteria provided, single submitter	clinical testing