Submissions for variant NM_024675.4(PALB2):c.12dup (p.Pro5fs)

dbSNP: rs879254062

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235308	SCV000293344	pathogenic	not provided	2022-08-15	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29922827, 27469594)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686286	SCV000813798	pathogenic	Familial cancer of breast	2024-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro5Serfs*8) 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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 27469594). This variant is also known as c.12_13insT. ClinVar contains an entry for this variant (Variation ID: 246045). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001010853	SCV001171107	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-17	criteria provided, single submitter	clinical testing	The c.12dupT pathogenic mutation, located in coding exon 1 of the PALB2 gene, results from a duplication of T at nucleotide position 12, causing a translational frameshift with a predicted alternate stop codon (p.P5Sfs*8). 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.
Color Diagnostics, LLC DBA Color Health	RCV001010853	SCV001344281	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-21	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 1 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant (also known as c.12_13insT in the literature) has been reported in an individual affected with breast cancer (PMID: 27469594). This variant has been identified in 1/247574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV000686286	SCV004187521	pathogenic	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525908	SCV005039462	pathogenic	Hereditary breast ovarian cancer syndrome	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.12dupT (p.Pro5SerfsX8) 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. The variant allele was found at a frequency of 4e-06 in 247574 control chromosomes. c.12dupT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Palmer_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32427313). ClinVar contains an entry for this variant (Variation ID: 246045). Based on the evidence outlined above, the variant was classified as pathogenic.