Submissions for variant NM_000535.7(PMS2):c.114G>A (p.Ala38=)

gnomAD frequency: 0.00001  dbSNP: rs558032755

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164989	SCV000215683	likely benign	Hereditary cancer-predisposing syndrome	2014-06-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000226046	SCV000285047	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000418737	SCV000515779	likely benign	not specified	2017-06-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418737	SCV000697280	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164989	SCV000903870	likely benign	Hereditary cancer-predisposing syndrome	2016-04-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164989	SCV002529760	likely benign	Hereditary cancer-predisposing syndrome	2022-01-07	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358201	SCV001553874	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The PMS2 p.Ala38= variant was not identified in the literature. The variant was identified in dbSNP (rs558032755) as “with uncertain significance allele” and ClinVar (interpreted as "likely benign" by Invitae and 3 others and "uncertain significance by Integrated Genetics). The variant was identified in control databases in 3 of 240,422 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 14,152 chromosomes (freq: 0.00007), East Asian in 2 of 17,130 chromosomes (freq: 0.0001), but not observed in the Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The variant was identified in our laboratory in an individual with a likely pathogenic PMS2 variant (p.Gln288Thrfs*11). The p.Ala38= variant is not expected to have clinical significance because it does not result in a change of amino acid.The variant occurs at a non-conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.