Submissions for variant NM_024675.4(PALB2):c.2982dup (p.Ala995fs)

dbSNP: rs180177127

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114576	SCV000267970	likely pathogenic	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Ambry Genetics	RCV000213482	SCV000273157	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-30	criteria provided, single submitter	clinical testing	The c.2982dupT pathogenic mutation, located in coding exon 9 of the PALB2 gene, results from a duplication of T at nucleotide position 2982, causing a translational frameshift with a predicted alternate stop codon (p.A995Cfs*16). This alteration has been identified in multiple high-risk breast cancer patients (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). This alteration was also identified in three high-risk patients undergoing pancreatic cancer screening; these individuals were diagnosed with breast or prostate cancer and had at least one first- or second-degree relative diagnosed with pancreatic cancer (Abe T et al. J. Clin. Oncol. 2019 05;37:1070-1080). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000114576	SCV000290857	pathogenic	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala995Cysfs*16) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17200668, 19264984, 23448497, 26283626, 26534844). ClinVar contains an entry for this variant (Variation ID: 126697). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000114576	SCV000487937	likely pathogenic	Familial cancer of breast	2015-12-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213482	SCV000685997	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 9 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 17200668, 21932393, 23423317, 23448497, 25099575, 26283626, 26534844, 33471991, 34113003) and pancreatic cancer (PMID: 30883245). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Sema4, Sema4	RCV000213482	SCV002530740	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	curation
GeneDx	RCV003229810	SCV003927295	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17200668, 19264984, 24206657, 30883245, 23448497, 21165770, 25099575, 26283626, 34113003, 33471991)
Myriad Genetics, Inc.	RCV000114576	SCV004019707	pathogenic	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000114576	SCV004202691	pathogenic	Familial cancer of breast	2024-03-15	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114576	SCV001193319	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.