Submissions for variant NM_000535.7(PMS2):c.355G>T (p.Asp119Tyr)

dbSNP: rs587781913

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130256	SCV000185100	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.D119Y variant (also known as c.355G>T), located in coding exon 5 of the PMS2 gene, results from a G to T substitution at nucleotide position 355. The aspartic acid at codon 119 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). 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.
GeneDx	RCV000221783	SCV000279969	uncertain significance	not provided	2016-03-10	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.355G>T at the cDNA level, p.Asp119Tyr (D119Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp119Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Asp119Tyr occurs at a position that is conserved in mammals and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Asp119Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000411252	SCV000489373	uncertain significance	Lynch syndrome 4	2016-09-27	criteria provided, single submitter	clinical testing
Invitae	RCV000532710	SCV000625647	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-25	criteria provided, single submitter	clinical testing	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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 141655). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). This variant is present in population databases (rs587781913, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 119 of the PMS2 protein (p.Asp119Tyr).
Myriad Genetics, Inc.	RCV000411252	SCV004019820	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	RCV000411252	SCV004205453	uncertain significance	Lynch syndrome 4	2023-09-08	criteria provided, single submitter	clinical testing