Submissions for variant NM_000535.7(PMS2):c.830C>A (p.Thr277Lys)

dbSNP: rs1805322

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082886	SCV000166392	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000128979	SCV000172865	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000586384	SCV000211576	likely benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25372392, 21153778, 22949387)
Eurofins Ntd Llc (ga)	RCV000586384	SCV000333805	uncertain significance	not provided	2015-09-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128979	SCV000686244	likely benign	Hereditary cancer-predisposing syndrome	2015-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586384	SCV000697389	benign	not provided	2016-02-01	criteria provided, single submitter	clinical testing	Variant summary: The c.830C>A variant affects a conserved nucleotide, resulting in amino acid change from Thr to Lys. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. Sequence comparison suggests exon 8 does not match to any pseudogene region with high homology. This variant is found predominantly in African population at a frequency of 0.0045 (46/10332), which is about 39 times of maximal expected frequency of a pathogenic allele (0.0001136), suggesting this variant is benign. In addition, multiple clinical laboratories/literature classified this variant as benign. Taken together, this variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586384	SCV001473153	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	The PMS2 c.830C>A; p.Thr277Lys variant (rs1805322) is reported as benign/likely benign by multiple laboratories in ClinVar (Variation ID: 135946). This variant is found in the African population with an allele frequency of 0.5% (114/24962 alleles) in the Genome Aggregation Database. The threonine at codon 277 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Although the evidence suggests this variant may be likely benign, there is currently insufficient information to classify with certainty. Therefore, based on available information, the clinical significance of this variant is uncertain at this time.
Genetic Services Laboratory, University of Chicago	RCV001818294	SCV002069909	likely benign	not specified	2021-02-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128979	SCV002530392	benign	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818294	SCV004025125	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000586384	SCV004223991	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing	BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492546	SCV004239604	likely benign	Breast and/or ovarian cancer	2022-11-22	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989321	SCV004807850	likely benign	Mismatch repair cancer syndrome 4	2024-03-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128979	SCV005415546	benign	Hereditary cancer-predisposing syndrome	2024-08-20	criteria provided, single submitter	clinical testing	The variant is observed in one or more well-documented healthy adults. The p.Thr277Lys variant is observed in 68/16,248 (0.4185%) alleles from individuals of gnomAD African background in gnomAD, which is greater than expected for the disorder. There is a moderate physicochemical difference between threonine and lysine. For these reasons, this variant has been classified as Benign.
All of Us Research Program, National Institutes of Health	RCV004806074	SCV005429626	likely benign	Lynch syndrome	2024-09-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586384	SCV005437059	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BS1
True Health Diagnostics	RCV000128979	SCV000788120	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing