Submissions for variant NM_024675.4(PALB2):c.2727_2728del (p.Thr911fs)

dbSNP: rs730881869

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254678	SCV000211479	pathogenic	not provided	2023-06-02	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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Lowery et al., 2018; Sun et al., 2017); This variant is associated with the following publications: (PMID: 28724667, 26681312, 29506128, 31447099, 32546565, 29922827, 33804961)
Ambry Genetics	RCV000160810	SCV000275628	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	The c.2727_2728delTT pathogenic mutation, located in coding exon 7 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 2727 to 2728, causing a translational frameshift with a predicted alternate stop codon (p.T911Lfs*16). This alteration has been identified in individuals diagnosed with breast cancer and a pancreatic exocrine neoplasm (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
Invitae	RCV000232116	SCV000290847	pathogenic	Familial cancer of breast	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr911Leufs*16) 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 (rs730881869, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182742). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254678	SCV000601769	pathogenic	not provided	2018-07-11	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000232116	SCV000840036	pathogenic	Familial cancer of breast	2018-02-24	criteria provided, single submitter	clinical testing	This c.2727_2728delTT (p.Thr911Leufs*16) frameshift variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two unrelated breast cancer patients (PMID 26681312 and 28724667). Moreover, four independent genetic diagnostic laboratories have categorized this variant as pathogenic/likely pathogenic (ClinVar database). Mono-allelic loss of function variants in the PALB2 gene have been associated with susceptibility to breast cancer and pancreatic cancer. Bi-allelic loss of function variants in this gene are associated with Fanconi anemia, complementation group N (OMIM 610832). This variant in the PALB2 gene is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000160810	SCV000903745	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 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. This variant has been reported in individuals affected with breast cancer (PMID: 26681312, 28724667, 31768816) and pancreatic cancer (PMID: 29506128). This variant has been identified in 1/251482 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193416	SCV001362217	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-12	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2727_2728delTT (p.Thr911LeufsX16) 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 (eg. c.2920_2921delAA, p.Lys974fsX5; c.3113G>A, p.Trp1038X). The variant allele was found at a frequency of 4.1e-06 in 246270 control chromosomes. c.2727_2728delTT has been reported in the literature in individuals affected with breast and pancreatic cancer (Lowery_2018, Sun_2017, Susswein_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000232116	SCV002556460	pathogenic	Familial cancer of breast	2020-04-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492637	SCV002794109	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-09-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232116	SCV004188516	pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000232116	SCV004202741	pathogenic	Familial cancer of breast	2022-04-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544473	SCV004768645	pathogenic	PALB2-related disorder	2024-03-01	criteria provided, single submitter	clinical testing	The PALB2 c.2727_2728delTT variant is predicted to result in a frameshift and premature protein termination (p.Thr911Leufs*16). This variant has been reported in individuals with breast cancer (Supplementary Table S3, Sun et al. 2017. PubMed ID: 28724667), exocrine pancreatic neoplasm (Lowery et al. 2018. PubMed ID: 29506128) and ovarian cancer (Supplementary Table 3, Song et al. 2021. PubMed ID: 32546565). This variant was identified in an individual referred for next-generation cancer panel testing and was classified as pathogenic (Supplementary Table S1, Susswein et al. 2016. PubMed ID: 26681312). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182742). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003162679	SCV002758442	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV004544473	SCV004228970	not provided	PALB2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-07-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.