Submissions for variant NM_000535.7(PMS2):c.1576G>T (p.Asp526Tyr)

gnomAD frequency: 0.00003  dbSNP: rs63750686

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165677	SCV000216415	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The p.D526Y variant (also known as c.1576G>T), located in coding exon 11 of the PMS2 gene, results from a G to T substitution at nucleotide position 1576. The aspartic acid at codon 526 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well 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	RCV000227646	SCV000285076	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 526 of the PMS2 protein (p.Asp526Tyr). This variant is present in population databases (rs63750686, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer, breast and/or ovarian cancer (PMID: 34326862, 35451682). ClinVar contains an entry for this variant (Variation ID: 186139). 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.
GeneDx	RCV000679352	SCV000568930	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (Dharwadkar et al., 2020); This variant is associated with the following publications: (PMID: 33359728)
Color Diagnostics, LLC DBA Color Health	RCV000165677	SCV000686142	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 526 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 7/251074 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.
PreventionGenetics, part of Exact Sciences	RCV000679352	SCV000806181	uncertain significance	not provided	2017-06-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679352	SCV001134582	uncertain significance	not provided	2019-01-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175050	SCV001338587	uncertain significance	not specified	2020-04-17	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1576G>T (p.Asp526Tyr) 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 2.8e-05 in 251074 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1576G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six 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.
Sema4, Sema4	RCV000165677	SCV002530206	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492663	SCV002792871	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-07-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462182	SCV004205475	uncertain significance	Lynch syndrome 4	2023-08-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995445	SCV004844178	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 526 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 7/251074 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.