Submissions for variant NM_024675.4(PALB2):c.2512C>T (p.Gln838Ter)

dbSNP: rs750650768

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561038	SCV000670662	pathogenic	Hereditary cancer-predisposing syndrome	2016-06-22	criteria provided, single submitter	clinical testing	The p.Q838* pathogenic mutation (also known as c.2512C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2512. This changes the amino acid from a glutamine to a stop codon within coding exon 5. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Color Diagnostics, LLC DBA Color Health	RCV000561038	SCV000690854	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 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.
Invitae	RCV001053672	SCV001217945	pathogenic	Familial cancer of breast	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln838*) 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 variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 484190). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553686	SCV001774643	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2512C>T (p.Gln838X) 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 was absent in 250478 control chromosomes. To our knowledge, no occurrence of c.2512C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 citing overlapping evidence criteria utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV001053672	SCV004186203	pathogenic	Familial cancer of breast	2023-09-13	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	RCV001053672	SCV004202702	likely pathogenic	Familial cancer of breast	2022-11-12	criteria provided, single submitter	clinical testing