Submissions for variant NM_000535.7(PMS2):c.229G>A (p.Glu77Lys)

gnomAD frequency: 0.00001  dbSNP: rs751235177

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215049	SCV000274188	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	The p.E77K variant (also known as c.229G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 229. The glutamic acid at codon 77 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463790	SCV000552070	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 77 of the PMS2 protein (p.Glu77Lys). This variant is present in population databases (rs751235177, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 230591). 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.
Counsyl	RCV000662890	SCV000785804	uncertain significance	Lynch syndrome 4	2017-12-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001547436	SCV001767141	uncertain significance	not provided	2023-12-12	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; Observed in both cases and controls in a breast cancer study (PMID: 33471991); This variant is associated with the following publications: (PMID: 33471991, 11574484)
Sema4, Sema4	RCV000215049	SCV002530283	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662890	SCV004019813	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320609	SCV004025135	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215049	SCV004359702	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 77 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. In a large breast cancer case-control study, this variant has been reported in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/250862 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	RCV003997851	SCV004842144	uncertain significance	Lynch syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 77 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. In a large breast cancer case-control study, this variant has been reported in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/250862 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.