Submissions for variant NM_024675.4(PALB2):c.2834+1G>T

dbSNP: rs587776419

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000133481	SCV000322191	likely pathogenic	not provided	2024-09-24	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 30890586); Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 25099575); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30890586, 25099575)
Counsyl	RCV000411304	SCV000488978	likely pathogenic	Familial cancer of breast	2016-07-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411304	SCV000633380	pathogenic	Familial cancer of breast	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the PALB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25099575, 26681312; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143968). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000567638	SCV000670660	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	The c.2834+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of the PALB2 gene. This alteration has previously been reported in one high-risk family with breast cancer (Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763377	SCV000894074	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411304	SCV004019217	likely pathogenic	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
SNPedia	RCV000133481	SCV000188555	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Leiden Open Variation Database	RCV000411304	SCV001193295	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.