Submissions for variant NM_024675.4(PALB2):c.751C>T (p.Gln251Ter)

gnomAD frequency: 0.00001  dbSNP: rs180177091

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210097	SCV000266112	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210097	SCV000277492	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-21	criteria provided, single submitter	clinical testing	The p.Q251* pathogenic mutation (also known as c.751C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 751. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been identified in several Chinese breast cancer cohorts (Cao AY et al. Breast Cancer Res. Treat. 2009 Apr;114(3):457-62; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Zhang K et al. Breast Cancer Res. Treat. 2017 Dec;166(3):865-873) and in one individual with papillary serous ovarian cancer (Norquist BM et al. JAMA Oncol 2016 Apr;2(4):482-90). 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.
GeneDx	RCV000413603	SCV000490684	pathogenic	not provided	2018-08-30	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted PALB2 c.751C>T at the cDNA level and p.Gln251Ter (Q251X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with early-onset breast cancer or ovarian cancer (Cao 2009, Tischkowitz 2010, Hasmad 2015, Norquist 2016, Sun 2017) and is considered pathogenic.
Counsyl	RCV000114657	SCV000785659	pathogenic	Familial cancer of breast	2017-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114657	SCV000960330	pathogenic	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln251*) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18446436, 26541979, 26720728, 28724667, 28825143). ClinVar contains an entry for this variant (Variation ID: 126767). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000114657	SCV001251427	pathogenic	Familial cancer of breast	2019-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210097	SCV001354212	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-28	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least eight individuals affected with breast and ovarian cancer (PMID: 18446436, 26541979, 26720728, 28724667, 28825143; Color internal data). 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.
Sema4, Sema4	RCV000210097	SCV002531217	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114657	SCV004019687	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.
Baylor Genetics	RCV000114657	SCV004202640	pathogenic	Familial cancer of breast	2023-05-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492446	SCV004239565	pathogenic	Breast and/or ovarian cancer	2023-06-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000114657	SCV005044121	pathogenic	Familial cancer of breast	2022-06-17	criteria provided, single submitter	clinical testing	The c.751C>T variant identified in PALB2 has previously been reported in multiple individuals affected with breast cancer [PMID: 18446436, 26541979, 26720728, 28724667, 28825143, 33646313, 32339256]. The variant has been deposited in ClinVar [ClinVar ID: 126767] as Pathogenic by multiple submitters. The c.751C>T variant is observed in 3 alleles (0.0003% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.751C>T variant is located in exon 4 of this 13-exon gene, predicted to incorporate a premature termination codon (p.(Gln251Ter)), and is expected to result in loss-of-function via nonsense-mediated decay. Multiple loss-of-function variants downstream to the c.751C>T variant have been reported in the literature and ClinVar in individuals with familial breast cancer. Based on available evidence this inherited c.751C>T p.(Gln251Ter) variant identified in PALB2 is classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796018	SCV005417706	pathogenic	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4
Leiden Open Variation Database	RCV000114657	SCV001193011	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.