Submissions for variant NM_000535.7(PMS2):c.988+11T>C

gnomAD frequency: 0.00032  dbSNP: rs139969671

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127458	SCV000171023	benign	not specified	2013-12-23	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.
Color Diagnostics, LLC DBA Color Health	RCV000579510	SCV000686263	benign	Hereditary cancer-predisposing syndrome	2016-06-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164299	SCV001326414	uncertain significance	Lynch syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002055749	SCV002403185	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579510	SCV002530414	likely benign	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	curation
Ambry Genetics	RCV000579510	SCV002690948	likely benign	Hereditary cancer-predisposing syndrome	2015-07-29	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000127458	SCV004025122	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492573	SCV004239609	likely benign	Breast and/or ovarian cancer	2023-05-23	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000127458	SCV001550955	benign	not specified		no assertion criteria provided	clinical testing	The PMS2 c.988+11T>C variant was not identified in the literature. The variant was identified in dbSNP (ID: rs139969671) “With Benign allele”, and ClinVar (classified benign by GeneDx and Color). The variant was identified in control databases in 163 (1 homozygous) of 276514 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24004 chromosomes (freq: 0.0002), Other in 6 of 6450 chromosomes (freq: 0.0009), European Non-Finnish in 19 of 126498 chromosomes (freq: 0.0002), East Asian in 12 of 18864 chromosomes (freq: 0.0006), European Finnish in 120 (1 homozygous) of 25446 chromosomes (freq: 0.005), and South Asian in 2 of 30744 chromosomes (freq: 0.00007) while not observed in the Latino and Ashkenazi Jewish populations. The variant occurs 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 this variant meets our laboratory's criteria to be classified as benign.