ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1129C>T (p.Gln377Ter)

dbSNP: rs929474806
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000792959 SCV000932290 pathogenic Familial cancer of breast 2023-07-31 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 640023). This premature translational stop signal has been observed in individual(s) with vestibular schwannoma (PMID: 34308366). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln377*) 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).
Department of Pediatrics, Memorial Sloan Kettering Cancer Center RCV000792959 SCV001478142 pathogenic Familial cancer of breast 2020-12-15 criteria provided, single submitter research
Ambry Genetics RCV002325498 SCV002607811 pathogenic Hereditary cancer-predisposing syndrome 2021-11-23 criteria provided, single submitter clinical testing The p.Q377* pathogenic mutation (also known as c.1129C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 1129. This changes the amino acid from a glutamine to a stop codon within coding exon 4. 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.
Myriad Genetics, Inc. RCV000792959 SCV003806612 pathogenic Familial cancer of breast 2023-01-19 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000792959 SCV004848672 likely pathogenic Familial cancer of breast 2022-06-27 criteria provided, single submitter clinical testing The p.Gln377X variant in PALB2 has not been previously reported in individuals with PALB2-associated cancers but has been reported by other clinical laboratories in ClinVar (Variation ID: 640023). It was absent from large population databases. This nonsense variant leads to a premature termination codon at position 377, 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 in PALB2-associated cancers, including autosomal dominant breast cancer. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant PALB2-associated cancers. ACMG/AMP Criteria applied: PM2_Supporting, PVS1.

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