Submissions for variant NM_000535.7(PMS2):c.1004A>T (p.Asn335Ile)

dbSNP: rs200513014

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167223	SCV000218060	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.N335I variant (also known as c.1004A>T), located in coding exon 10 of the PMS2 gene, results from an A to T substitution at nucleotide position 1004. The asparagine at codon 335 is replaced by isoleucine, an amino acid with dissimilar properties. In a cohort of 1208 Icelandic individuals with colon cancer, this alteration was detected in one individual whose tumor demonstrated presence of all four mismatch repair proteins on immunohistochemistry (Haraldsdottir S et al. Nat Commun, 2017 May;8:14755). This alteration was also detected in 1 individual from 274 families with hereditary colon cancer; however, the alteration was not detected in an affected relative (Hansen MF et al. Clin. Genet., 2017 Oct;92:405-414). This amino acid position is highly 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	RCV000465798	SCV000551936	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-06-29	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. 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: 187489). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28466842). This variant is present in population databases (rs200513014, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 335 of the PMS2 protein (p.Asn335Ile).
Color Diagnostics, LLC DBA Color Health	RCV000167223	SCV000909662	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818398	SCV002069658	uncertain significance	not specified	2021-01-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1004A>T, in exon 10 which results in an amino acid change, p.Asn335Ile. This sequence change has been described in the gnomAD database in one individual with an overall population frequency of 0.0004% (dbSNP rs200513014). The p.Asn335Ile change has been described in an individual with colorectal cancer (PMID: 28466842). Additionally, a different amino acid change at the same location (p.Asn335Ser) has been reported in association with breast and/or ovarian cancer (PMID: 24549055). The p.Asn335Ile change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Asn335Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn335Ile change remains unknown at this time.