Submissions for variant NM_000535.7(PMS2):c.1197G>A (p.Lys399=)

gnomAD frequency: 0.00004  dbSNP: rs757730609

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163177	SCV000213698	likely benign	Hereditary cancer-predisposing syndrome	2014-10-10	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	RCV001083265	SCV000285050	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163177	SCV000686104	likely benign	Hereditary cancer-predisposing syndrome	2016-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855624	SCV000697283	benign	not specified	2022-06-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590214	SCV000884401	likely benign	not provided	2017-09-16	criteria provided, single submitter	clinical testing	The c.1197G>A; p.Lys399Lys variant (rs757730609) does not alter the amino acid sequence of the PMS2 protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant has not been reported in association with any hereditary cancer syndromes in the medical literature or in gene specific variation databases. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the European Non-Finnish population (identified on 19 out of 125,472 chromosomes), and has been reported to the ClinVar database as a likely benign variant (Variation ID: 184060). Based on these observations, the p.Lys399Lys variant is likely to be benign.
GeneDx	RCV000590214	SCV001914086	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163177	SCV002529765	likely benign	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590214	SCV004010654	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492672	SCV004239579	likely benign	Breast and/or ovarian cancer	2022-07-25	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000163177	SCV000788099	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358475	SCV001554220	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Lys399= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs757730609) as “With Uncertain significance allele”, ClinVar (as likely benign by Ambry Genetics, Invitae, Color Genomics, ARUP Laboratories, and True Health Diagnostics, and as uncertain significacne by Integrated Genetics . The variant was identified in control databases in 19 of 275194 chromosomes at a frequency of 0.000069 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 19 of 125472 chromosomes (freq: 0.000151), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Lys399= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.