Submissions for variant NM_024675.4(PALB2):c.3286_3289delinsGTTAATGA (p.Asn1096fs)

dbSNP: rs587782337

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206761	SCV000260756	pathogenic	Familial cancer of breast	2022-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1096Valfs*4) 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 variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1075106). Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000217334	SCV000275016	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-25	criteria provided, single submitter	clinical testing	The c.3286_3289delAACCinsGTTAATGA pathogenic mutation, located in coding exon 12 of the PALB2 gene, results from the deletion of 4 nucleotides and insertion of 8 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.N1096Vfs*4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507665	SCV000601780	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in an individual with an individual with a hereditary breast and ovarian cancer (HBOC) syndrome related disorder (PMID: 24763289 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000217334	SCV000686024	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-28	criteria provided, single submitter	clinical testing	This variant causes a replacement of 4 nucleotides at c.3286_3289 positions in exon 12 of the PALB2 gene with GTTAATGA, creating a frameshift and premature translation stop signal. This variant is expected to truncate the carboxyl terminus of the protein that functions in BRCA2 and RAD-51 interactions (PMID: 25833843) and may trigger nonsense-mediated decay. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. **However, other truncations at the carboxyl terminus of PALB2 after the position of this variant have been reported in at least 20 individuals and families affected breast and/or ovarian cancer (PMID: 17200668, 25099575, 25452441, 26315354, 28281021) and in compound heterozygous carriers affected with Fanconi anemia (PMID: 17200671).** 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586640	SCV000699588	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3286_3289delinsGTTAATGA (p.Asn1096ValfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251488 control chromosomes. c.3286_3289delinsGTTAATGA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (LaDuca_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000507665	SCV000778904	pathogenic	not provided	2023-01-20	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 in large population cohorts (gnomAD); Reported in the literature in individuals referred for hereditary cancer testing (LaDuca et al., 2017); This variant is associated with the following publications: (PMID: 24763289)
Myriad Genetics, Inc.	RCV000206761	SCV004188515	pathogenic	Familial cancer of breast	2023-09-14	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	RCV000206761	SCV004202102	pathogenic	Familial cancer of breast	2023-09-03	criteria provided, single submitter	clinical testing