Submissions for variant NM_024675.4(PALB2):c.1675_1676delinsTG

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235193	SCV000149979	pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Bonache et al., 2018; Momozawa et al., 2018; Abe et al., 2021; Botrus et al., 2022); Nonsense 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26681312, 28152038, 30287823, 30306255, 30792206, 31589614, 33413558, 35238112, 36359225)
Ambry Genetics	RCV000116070	SCV000214781	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-25	criteria provided, single submitter	clinical testing	The c.1675_1676delCAinsTG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from an in-frame deletion of CA and insertion of TG at nucleotide positions 1675 and 1676. This changes the glutamine at codon 559 to a stop codon (p.Q559*). This mutation was identified in a breast cancer proband from a cohort of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18(8):823-32). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635816	SCV000757239	pathogenic	Familial cancer of breast	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln559*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 128121). For these reasons, this variant has been classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722029	SCV000853206	pathogenic	Precursor B-cell acute lymphoblastic leukemia	2016-11-18	criteria provided, single submitter	clinical testing	This is a nonsense alteration in which coding positions 1675 and 1676 are deleted and replaced by TG. This alteration is predicted to change a Glutamine to a premature stop codon at amino acid codon 559. Classification criteria: PVS1, PS3, PM2.
Color Diagnostics, LLC DBA Color Health	RCV000116070	SCV000905191	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual with breast cancer (PMID: 26681312) and in an individual with familial pancreatic cancer (PMID: 33413558). 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	RCV001280657	SCV001467940	pathogenic	Malignant tumor of breast	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1675_1676delinsTG (p.Gln559X) 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 allele was found at a frequency of 8e-06 in 250092 control chromosomes. c.1675_1676delinsTG has been reported in the literature in at least one individual affected with Breast Cancer (e.g. Susswein_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490784	SCV002795441	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-12-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000635816	SCV004188496	pathogenic	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235193	SCV004222269	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	This variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26681312 (2015)) and pancreatic cancer (PMID: 33413558 (2021)). 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.
PreventionGenetics, part of Exact Sciences	RCV004739404	SCV005360474	pathogenic	PALB2-related disorder	2024-07-12	no assertion criteria provided	clinical testing	The PALB2 c.1675_1676delinsTG variant is predicted to result in premature protein termination (p.Gln559*). This variant has been reported in multiple large cancer studies (see example: Table S1, Susswein et al. 2016. PubMed ID: 26681312; Abe et al. 2021. PubMed ID: 33413558). This variant is not present in a large population database and is reported  as pathogenic in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128121/). Nonsense variants in PALB2 are expected to be pathogenic. Given all the evidence, we interpret c.1675_1676delinsTG (p.Gln559*) as pathogenic.