ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2962C>T (p.Gln988Ter)

dbSNP: rs118203999
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129469 SCV000184239 pathogenic Hereditary cancer-predisposing syndrome 2022-08-29 criteria provided, single submitter clinical testing The p.Q988* pathogenic mutation (also known as c.2962C>T) located in coding exon 9 of the PALB2 gene, results from a C to T substitution at nucleotide position 2962. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation was described in a child with Fanconia anemia, whose clinical features included medulloblastoma, growth retardation, microcephaly, and hypoplastic thumb (Reid S et al. Nat. Genet. 2007; 39:162-4). This mutation has also been described in a patient with pre-menopausal breast cancer who had a paternal family history of pancreatic cancer (father and paternal aunt) and maternal family history of post-menopausal breast cancer (mother and two maternal aunts) (Hofstatter EW et al. Fam. Cancer 2011; 10:225-31). This mutation was also shown to segregate with disease in twin sisters with breast cancer in their forties and in their mother with bilateral breast cancer in her late fifties/early 60s (Hellebrand H et al. Hum. Mutat. 2011; 32:E2176-88). 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 RCV000657596 SCV000779336 pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2962C>T at the cDNA level and p.Gln988Ter (Q988X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 Gln988Ter has been reported in individuals with familial breast cancer and in the parent of a child with Fanconi anemia (Reid 2007, Hellebrand 2011, Hofstatter 2011). This variant is considered pathogenic.
Counsyl RCV000662710 SCV000785458 pathogenic Familial cancer of breast 2017-08-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000662710 SCV000835984 pathogenic Familial cancer of breast 2023-09-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln988*) 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: 21365267, 21618343). ClinVar contains an entry for this variant (Variation ID: 1246). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000129469 SCV001342840 pathogenic Hereditary cancer-predisposing syndrome 2023-11-20 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 9 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 four individuals affected with breast cancer from two families and observed to segregate with disease in a mother and her two daughters (PMID: 21365267, 21618343), and this variant also has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_000013). This variant also has been detected in a parent of a child affected with Fanconi anemia, whose other parent has a different pathogenic truncation variant in PALB2 (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.
Genetics and Molecular Pathology, SA Pathology RCV000662710 SCV002556380 pathogenic Familial cancer of breast 2020-05-05 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000662710 SCV004019763 pathogenic Familial cancer of breast 2023-04-03 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.
OMIM RCV000001306 SCV000021456 pathogenic Fanconi anemia complementation group N 2007-02-01 no assertion criteria provided literature only
OMIM RCV000001307 SCV000021457 risk factor Breast cancer, susceptibility to 2007-02-01 no assertion criteria provided literature only
Leiden Open Variation Database RCV000657596 SCV001193316 pathogenic not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz.

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