Submissions for variant NM_024675.4(PALB2):c.2759T>G (p.Leu920Ter)

dbSNP: rs1567214493

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780562	SCV000917942	likely pathogenic	Familial cancer of breast	2018-10-29	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2759T>G (p.Leu920X) 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 (e.g. c.2920_2921delAA (p.Lys974fsX5), c.3113G>A (p.Trp1038X), c.3323delA (p.Tyr1108fsX16)). The variant was absent in 244700 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2759T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000780562	SCV002205960	pathogenic	Familial cancer of breast	2023-07-29	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: 632929). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu920*) 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).
Ambry Genetics	RCV002440616	SCV002752173	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-28	criteria provided, single submitter	clinical testing	The p.L920* pathogenic mutation (also known as c.2759T>G), located in coding exon 8 of the PALB2 gene, results from a T to G substitution at nucleotide position 2759. This changes the amino acid from a leucine to a stop codon within coding exon 8. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.	RCV000780562	SCV004186194	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.