Submissions for variant NM_024675.4(PALB2):c.2325dup (p.Phe776fs)

dbSNP: rs876659997

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218689	SCV000277043	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-02	criteria provided, single submitter	clinical testing	The c.2325dupA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a duplication of A at nucleotide position 2325, causing a translational frameshift with a predicted alternate stop codon (p.F776Ifs*26). This alteration has been described in individuals with hereditary breast cancer and ovarian cancer (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22(11):1305-13; Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149(2):547-54; Kotsopoulos J. Fam. Cancer 2017 01;16(1):29-34; Girard E et al. Int J Cancer. 2019 Apr 15;144(8):1962-1974). Of note, this mutation is also designated as c.2325_2326insA in published literature. 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.
GeneDx	RCV000236131	SCV000292653	pathogenic	not provided	2023-09-28	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25575445, 24549055, 27631815, 24870022, 30772928, 30322717, 28779002, 32546565, 30303537, 33804961, 34113003)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468481	SCV000550697	pathogenic	Familial cancer of breast	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe776Ilefs*26) 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 hereditary breast and/or ovarian cancer (PMID: 24549055, 25575445). ClinVar contains an entry for this variant (Variation ID: 232803). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236131	SCV000601755	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218689	SCV000690842	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 5 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 and/or ovarian cancer (PMID: 24549055, 25575445, 27631815, 34113003). This variant also has been detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010234). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798719	SCV002043593	pathogenic	Breast and/or ovarian cancer	2021-05-10	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000468481	SCV002761571	pathogenic	Familial cancer of breast	2021-03-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532801	SCV004103900	pathogenic	PALB2-related disorder	2023-10-05	criteria provided, single submitter	clinical testing	The PALB2 c.2325dupA variant is predicted to result in a frameshift and premature protein termination (p.Phe776Ilefs*26). This variant has been reported in individuals with hereditary breast and ovarian cancer syndrome (Table 4, Castéra et al. 2014. PubMed ID: 24549055; Table 1, Kotsopoulos et al. 2017. PubMed ID: 27631815; Table 1, Nguyen-Dumont et al. 2015. PubMed ID: 25575445). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/232803/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV000468481	SCV004189409	pathogenic	Familial cancer of breast	2023-09-12	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	RCV000468481	SCV004202159	pathogenic	Familial cancer of breast	2023-07-24	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000468481	SCV001193213	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.