Submissions for variant NM_024675.4(PALB2):c.1347A>G (p.Lys449=)

dbSNP: rs587780205

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590184	SCV000149975	uncertain significance	not provided	2021-10-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with breast cancer (Decker 2017); This variant is associated with the following publications: (PMID: 28779002)
Ambry Genetics	RCV000116066	SCV000186224	likely benign	Hereditary cancer-predisposing syndrome	2018-11-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087089	SCV000255076	likely benign	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590184	SCV000699521	uncertain significance	not provided	2016-05-20	criteria provided, single submitter	clinical testing	Variant summary: The c.1347A>G (p.Lys449=) in PALB2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant enhance a cryptic donor splices site, however these predictions are yet to be confirmed by the functional studies. The variant is absent from the control population dataset of ExAC, suggesting that it is not a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via published reports, but is cited as VUS/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000116066	SCV000903224	likely benign	Hereditary cancer-predisposing syndrome	2016-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818286	SCV002065762	uncertain significance	not specified	2021-11-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356241	SCV001551356	uncertain significance	Pancreatic cancer, susceptibility to, 3		no assertion criteria provided	clinical testing	The PALB2 p.Lys449= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs587780205) as "With Uncertain significance allele" and ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 1 of 245422 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111034 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Lys449= 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. However, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.