Submissions for variant NM_024675.4(PALB2):c.79G>T (p.Glu27Ter)

gnomAD frequency: 0.00002  dbSNP: rs878855122

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228882	SCV000290889	pathogenic	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu27*) 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 (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with vulvar and breast cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 241570). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000255635	SCV000321924	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	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); This variant is associated with the following publications: (PMID: 26023681, 31159747, 29785153, 29625052, 33084842, 29922827)
Ambry Genetics	RCV000454231	SCV000538180	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-04	criteria provided, single submitter	clinical testing	The p.E27* pathogenic mutation (also known as c.79G>T), located in coding exon 2 of the PALB2 gene, results from a G to T substitution at nucleotide position 79. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This pathogenic mutation was reported in a patient diagnosed with breast cancer at age 68 who also had a family history of breast, pancreatic, prostate, and stomach cancer (Foley SB et al. EBioMedicine. 2015 Jan;2(1):74-81). This has also been reported in a Romanian cohort of individuals diagnosed with breast cancer (Goidescu IG et al. Clujul Med. 2018 Apr;91:157-165). 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.
GeneKor MSA	RCV000454231	SCV000821763	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Glutamate to a premature translational stop signal at codon 27 of the PALB2 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has been described in the international literature in the individual with vulvar and breast cancer (PMID:26023681) and in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 241570).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175093	SCV001338663	pathogenic	Malignant tumor of breast	2020-04-23	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.79G>T (p.Glu27X) 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 251476 control chromosomes. c.79G>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Goidescu_2018) and an individual with a history of both breast and vulvar cancers (Foley_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Color Diagnostics, LLC DBA Color Health	RCV000454231	SCV001357310	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 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 identified in 2/251476 chromosomes 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255635	SCV001447126	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000454231	SCV002531222	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-25	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002500815	SCV002797291	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000228882	SCV004188483	pathogenic	Familial cancer of breast	2023-09-05	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.
Baylor Genetics	RCV000228882	SCV004202618	pathogenic	Familial cancer of breast	2023-05-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003485568	SCV004237476	pathogenic	Fanconi anemia complementation group N	2023-07-12	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000228882	SCV004848157	likely pathogenic	Familial cancer of breast	2018-03-23	criteria provided, single submitter	clinical testing	The p.Glu27X variant in PALB2 has been reported in 1 individual with vulvar and breast cancer (Foley 2015). The variant has been identified in 2/15302 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs878855122). However, this frequency is low enough to be consistent with the frequency of breast cancer in the general population. This nonsense variant leads to a premature termination codon at position 27, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PALB2 gene is an established disease mechanism in inherited predisposition to breast cancer. In summary, this variant meets criteria to be classified as likely pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PM2.
Molekularpathologisches Zentrum, Universitaetsklinikum Heidelberg	RCV002282082	SCV002571108	pathogenic	Lung cancer		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532964	SCV004119426	pathogenic	PALB2-related disorder	2024-02-06	no assertion criteria provided	clinical testing	The PALB2 c.79G>T variant is predicted to result in premature protein termination (p.Glu27*). This variant has been previously reported in individuals with personal and/or family history of breast and other cancer types (Foley et al. 2015. PubMed ID: 26023681; Huang et al. 2018. PubMed ID: 29625052, Table S2A; Tsaousis et al. 2019. PubMed ID: 31159747, Table S2; Goidescu et al. 2018. PubMed ID: 29785153). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/241570/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.