Submissions for variant NM_024675.4(PALB2):c.1924del (p.Met642fs)

dbSNP: rs730881865

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212803	SCV000211473	pathogenic	not provided	2021-04-23	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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24136930, 24415441, 26681312, 32339256, 31206626)
Ambry Genetics	RCV000160805	SCV000215660	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	The c.1924delA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1924, causing a translational frameshift with a predicted alternate stop codon (p.M642Cfs*18). This alteration was observed in multiple individuals and families with high risk breast cancer and at least one control across several studies (Janatova M et al. Cancer Epidemiol Biomarkers Prev, 2013 Dec;22:2323-32; Fernandes PH et al. Cancer, 2014 Apr;120:963-7; Susswein LR et al. Genet Med, 2016 08;18:823-32; Weitzel JN et al. Cancer, 2019 08;125:2829-2836; Zhou J et al. Cancer, 2020 07;126:3202-3208). 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.
Counsyl	RCV000410708	SCV000488110	likely pathogenic	Familial cancer of breast	2015-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000410708	SCV000757340	pathogenic	Familial cancer of breast	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met642Cysfs*18) 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 present in population databases (rs730881865, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 24136930, 24415441, 26681312). ClinVar contains an entry for this variant (Variation ID: 182738). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000160805	SCV002530657	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410708	SCV004019204	pathogenic	Familial cancer of breast	2023-03-30	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	RCV000410708	SCV004202689	pathogenic	Familial cancer of breast	2022-12-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212803	SCV004222278	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/250632 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer(PMIDs: 32339256 (2020), 31206626 (2019), 26681312 (2015), 24136930 (2013)). Based on the available information, this variant is classified as pathogenic.
Leiden Open Variation Database	RCV000410708	SCV001193169	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.