Submissions for variant NM_024675.4(PALB2):c.2514+3A>G

gnomAD frequency: 0.00001  dbSNP: rs515726088

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160843	SCV000211518	uncertain significance	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis 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; This variant is associated with the following publications: (PMID: 22692731, 25186627, 35610400)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114530	SCV000633356	uncertain significance	Familial cancer of breast	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs515726088, gnomAD 0.003%). This variant has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 22692731, 25186627, 35610400). ClinVar contains an entry for this variant (Variation ID: 126655). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000573333	SCV000663322	likely benign	Hereditary cancer-predisposing syndrome	2023-11-16	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.
Color Diagnostics, LLC DBA Color Health	RCV000573333	SCV001340937	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +3 position of intron 5 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 22692731, 25186627). This variant has been identified in 2/250064 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149781	SCV003838713	uncertain significance	Breast and/or ovarian cancer	2021-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000114530	SCV004202688	uncertain significance	Familial cancer of breast	2022-12-19	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114530	SCV001193241	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.