Submissions for variant NM_000535.7(PMS2):c.328G>T (p.Ala110Ser)

gnomAD frequency: 0.00002  dbSNP: rs767775907

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220893	SCV000279857	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Yehia et al., 2018; Paduano et al., 2022); This variant is associated with the following publications: (PMID: 35886069, 11574484, 29684080)
Invitae	RCV000630099	SCV000751055	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-15	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs767775907, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 110 of the PMS2 protein (p.Ala110Ser). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 234814).
Fulgent Genetics, Fulgent Genetics	RCV000765969	SCV000897390	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001019709	SCV001181101	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	The p.A110S variant (also known as c.328G>T), located in coding exon 4 of the PMS2 gene, results from a G to T substitution at nucleotide position 328. The alanine at codon 110 is replaced by serine, an amino acid with similar properties. This alteration has been observed in one individual from a cohort of patients with Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). This alteration was also detected in 2 breast cancer patients from 104 cases of familial cancer in an Italian cohort (Paduano F et al. Genes (Basel), 2022 Jul;13:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001019709	SCV001360038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 110 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29684080, 35886069). This variant has been identified in 4/235996 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.
All of Us Research Program, National Institutes of Health	RCV003998643	SCV004842126	uncertain significance	Lynch syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 110 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29684080, 35886069). This variant has been identified in 4/235996 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.