Submissions for variant NM_024675.4(PALB2):c.1240C>T (p.Arg414Ter)

gnomAD frequency: 0.00001  dbSNP: rs180177100

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254674	SCV000149973	pathogenic	not provided	2023-06-22	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; 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: 21285249, 23935836, 21207249, 25099575, 25525159, 24136930, 23935381, 24870022, 26720728, 27067391, 25619955, 27553368, 28024868, 28528518, 26681312, 22692731, 24448499, 25186627, 20412113, 21165770, 21618343, 29945567, 28779002, 29470806, 28724667, 29706558, 30067863, 30322717, 32426482, 32339256, 31589614, 32885271, 34308104, 36003761, 35753512, 30130155, 32853339, 29922827, 32997802, 28888541, 35264596, 31467304, 31619740, 36988593, 35118230, 36978154, 35875117, 36278678, 35685475, 35798629)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123331	SCV000166641	pathogenic	Familial cancer of breast	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg414*) 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 (rs180177100, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 21165770, 21285249, 21618343, 22692731, 24136930, 24448499). ClinVar contains an entry for this variant (Variation ID: 128117). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000116064	SCV000186556	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	The p.R414* pathogenic mutation (also known as c.1240C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in pancreatic, breast, and ovarian cancer patients to date, including multiple individuals with family histories significant for PALB2-related cancers (Slater EP et al. Clin. Genet. 2010 Nov;78:490-4; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Bogdanova N et al. Breast Cancer Res. Treat. 2011 Apr;126:545-50; Hellebrand H et al. Hum. Mutat. 2011 Jun;32:E2176-88; Janatova M et al. Cancer Epidemiol. Biomarkers Prev. 2013 Dec;22:2323-32; Kanchi KL et al. Nat. Commun. 2014;5:3156; Antoniou AC et al. N. Engl. J. Med. 2014 Oct;371(17):1651-2; Tung N et al. Cancer. 2015 Jan;121:25-33; Pinto P et al. Breast Cancer Res.Treat. 2016 Sep;159:245-56; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). 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	RCV000123331	SCV000488968	pathogenic	Familial cancer of breast	2016-07-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254674	SCV000601725	pathogenic	not provided	2021-03-05	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 and families with breast cancer or pancreatic ductal adenocarcinoma in the published literature (PMID: 30067863 (2018), 29470806 (2018), 28528518 (2017), 25186627 (2015), 21618343 (2011)). The frequency of this variant in the general population, 0.000029 (1/34586 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002477287	SCV000611291	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116064	SCV000685862	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-29	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 individuals affected with breast cancer (PMID: 21165770, 21285249, 21618343, 24136930, 25099575, 25186627, 26681312, 27553368, 29470806, 30128536, 33471991), pancreatic cancer (PMID: 20412113, 27449771, 30067863), and ovarian cancer (PMID: 24448499). In a breast cancer case-control study, PALB2 p.Arg414* was detected in 22/64,780 cases and 3/49,825 unaffected controls (OR 5.89, 95%CI 1.76-19.74, p = 0.004) (PMID: 31467304). This variant has been identified in 2/250782 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588541	SCV000699526	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1240C>T (p.Arg414X) 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 7.9e-06 in 252702 control chromosomes. c.1240C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bogdanova_2011, Casadei_2011, Susswein_2015, Norquist_2016, Sun_2017). 12 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.
Mendelics	RCV000116064	SCV000839042	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254674	SCV001247805	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254674	SCV001446611	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000123331	SCV001499700	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000123331	SCV002512645	pathogenic	Familial cancer of breast	2021-11-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254674	SCV002551680	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000123331	SCV002761569	pathogenic	Familial cancer of breast	2020-04-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123331	SCV004019641	pathogenic	Familial cancer of breast	2023-03-31	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000123331	SCV004027759	pathogenic	Familial cancer of breast	2023-07-18	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Baylor Genetics	RCV000123331	SCV004202064	pathogenic	Familial cancer of breast	2023-12-10	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555854	SCV005045091	pathogenic	Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2023-12-06	criteria provided, single submitter	clinical testing	The PALB2 c.1240C>T (p.Arg414Ter) variant has been reported in over 10 individuals with breast, ovarian, and pancreatic cancer (Antoniou AC et al., PMID: 25099575; Blanco A et al., PMID: 23935836; Bogdanova N et al., PMID: 21165770; Casadei S et al., PMID: 21285249; Catucci I et al., PMID: 22692731; Hellebrand H et al., PMID: 21618343; Janatova M et al., PMID: 24136930; Kanchi KL et al., PMID: 24448499; Schneider R et al., PMID: 21207249). This nonsense variant generates a premature stop codon that is predicted to result in nonsense mediated decay in a gene for which loss of function is a known mechanism of disease. This variant is only observed on 2/250,782 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a pathogenic variant in by 21 submitters (ClinVar Variation ID: 128117). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Institute of Immunology and Genetics Kaiserslautern	RCV004668783	SCV005093856	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-07-31	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000254674	SCV005197090	pathogenic	not provided	2024-02-23	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000254674	SCV001193079	pathogenic	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354096	SCV001548625	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Arg414X variant was identified in 9 of 5690 proband chromosomes (frequency: 0.0016) from individuals or families with breast and or ovarian cancer negative for BRCA1 and BRCA2 genes mutations and familial pancreatic cancer (Hellebrand 2011 PMID:21618343, Bogdanova 2011 PMID:21165770, Casadei 2011 PMID:21285249, Slater 2010 PMID:20412113, Janatova 2013 PMID:24136930, Antoniou 2014 PMID:25099575). The variant was also identified in the following databases: dbSNP (ID: rs180177100) as “With Pathogenic allele”, ClinVar (6x classified as pathogenic by GeneDx, Invitae, Ambry Genetics, Counsyl, Quest Diagnostics, Fulgent Genetics), Clinvitae (3x as pathogenic by ClinVar and Invitae), LOVD 3.0 (9x, reported as "affects function") and Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 2 of 245860 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 1 of 33574 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 111392 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg414X variant leads to a premature stop codon at position 414 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast, ovarian and pancreatic cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
BRCAlab, Lund University	RCV000588541	SCV002588987	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162546	SCV002758152	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004529946	SCV004710969	pathogenic	PALB2-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The PALB2 c.1240C>T variant is predicted to result in premature protein termination (p.Arg414*). This variant has been reported in multiple individuals with pancreatic or breast or ovarian cancer (see for example: Slater et al. 2010. PubMed ID: 20412113; Bogdanova et al. 2010. PubMed ID: 21165770; Casadei et al. 2011. PubMed ID: 21285249; Kanchi et al. 2014. PubMed ID: 24448499). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Multiple independent submitters in the ClinVar database interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/128117/). Nonsense variants in PALB2 are expected to be pathogenic. In summary, this variant is interpreted as pathogenic.