Submissions for variant NM_000535.7(PMS2):c.250A>C (p.Thr84Pro)

dbSNP: rs1554304938

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563874	SCV000664963	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-15	criteria provided, single submitter	clinical testing	The p.T84P variant (also known as c.250A>C), located in coding exon 3 of the PMS2 gene, results from an A to C substitution at nucleotide position 250. The amino acid change results in threonine to proline at codon 84, an amino acid with highly similar properties. This nucleotide position and amino acid position are not well conserved in available vertebrate species. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing; however, RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was reported in a cohort of Moroccan triple negative breast cancer patients (Laraqui A et al. J Genomics, 2021 Sep;9:43-54). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055075	SCV001219440	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 84 of the PMS2 protein (p.Thr84Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34646395). ClinVar contains an entry for this variant (Variation ID: 480955). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Sema4, Sema4	RCV000563874	SCV002530312	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
Baylor Genetics	RCV003465184	SCV004207844	uncertain significance	Lynch syndrome 4	2024-01-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000909	SCV004842137	uncertain significance	Lynch syndrome	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 84 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 been reported in a cohort of individuals affected with triple negative breast cancer (PMID: 34646395). 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.
GeneDx	RCV004701659	SCV005201447	uncertain significance	not provided	2023-11-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11574484, 34646395, 33471991)