Submissions for variant NM_000535.7(PMS2):c.1714G>A (p.Ala572Thr)

gnomAD frequency: 0.00009  dbSNP: rs63751023

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165566	SCV000216300	likely benign	Hereditary cancer-predisposing syndrome	2020-04-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000513405	SCV000565789	uncertain significance	not provided	2024-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer, Lynch syndrome-related cancers and/or polyps, or other cancers (PMID: 31391288, 35089076, 25980754, 35449176); This variant is associated with the following publications: (PMID: 17016615, 22290698, 24362816, 35089076, 31391288, 25980754, 35449176)
CeGaT Center for Human Genetics Tuebingen	RCV000513405	SCV000609249	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000662642	SCV000785329	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165566	SCV000910898	likely benign	Hereditary cancer-predisposing syndrome	2015-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193214	SCV001361921	uncertain significance	not specified	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1714G>A (p.Ala572Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251334 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Lynch Syndrome (8e-05 vs 0.00011), allowing no conclusion about variant significance. c.1714G>A has been reported in the literature in individuals affected with Lynch Syndrome-associated cancers and/or polyps (e.g. Yurgelun_2015, Li_2020, Sahin_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifiying the variant as either VUS (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150024	SCV003837729	uncertain significance	Breast and/or ovarian cancer	2021-11-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662642	SCV004019792	likely benign	Lynch syndrome 4	2024-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
All of Us Research Program, National Institutes of Health	RCV003995430	SCV004844147	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483538	SCV004228534	not provided	Lynch syndrome; Mismatch repair cancer syndrome 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-18-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.