Submissions for variant NM_024675.4(PALB2):c.3469C>T (p.Gln1157Ter)

dbSNP: rs1597062038

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001020375	SCV001181848	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	The p.Q1157* pathogenic mutation (also known as c.3469C>T), located in coding exon 13 of the PALB2 gene, results from a C to T substitution at nucleotide position 3469. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 30 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860983	SCV002227067	pathogenic	Familial cancer of breast	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1157*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 823806). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Ser1165*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226417	SCV003923192	likely pathogenic	Malignant tumor of breast	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3469C>T (p.Gln1157X) results in a premature termination codon, predicted to cause a truncation of the encoded protein disrupting Partner and localiser of BRCA2, WD40 domain, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr1183X). The variant was absent in 251476 control chromosomes. To our knowledge, no occurrence of c.3469C>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 likely pathogenic.
Myriad Genetics, Inc.	RCV001860983	SCV004189340	pathogenic	Familial cancer of breast	2023-09-15	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	RCV001860983	SCV004202745	likely pathogenic	Familial cancer of breast	2022-04-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001020375	SCV004357804	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the BRCA2 and RAD51 binding domains which have been reported to be essential in the homology directed repair pathway. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.