Submissions for variant NM_024675.4(PALB2):c.226del (p.Ile76fs)

dbSNP: rs587782443

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131508	SCV000186500	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	The c.226delA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 226, causing a translational frameshift with a predicted alternate stop codon (p.I76Yfs*101). This alteration was detected in 3/5054 African American women with breast cancer and 0/4993 unaffected controls (Palmer JR et al. J Natl Cancer Inst, 2020 12;112:1213-1221). This alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N Engl J Med, 2016 Aug;375:443-53). This alteration was also identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med, 2016 08;18:823-32). 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.
GeneDx	RCV000254673	SCV000211482	pathogenic	not provided	2023-03-30	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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27433846, 26681312, 28152038, 32427313, 31447099, 29922827)
Counsyl	RCV000411345	SCV000488062	likely pathogenic	Familial cancer of breast	2015-12-17	criteria provided, single submitter	clinical testing
Invitae	RCV000411345	SCV000633340	pathogenic	Familial cancer of breast	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile76Tyrfs*101) 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 (rs587782443, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 142408). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131508	SCV000685937	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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 one individual each affected with prostate cancer and referred for cancer panel testing without a personal history of cancer (PMID: 26681312, 27433846). This variant has been identified in 1/244238 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.
Mendelics	RCV000131508	SCV000839056	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254673	SCV000888368	pathogenic	not provided	2018-06-13	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258080	SCV001434919	pathogenic	Pancreatic cancer, susceptibility to, 3; Breast cancer, susceptibility to	2018-10-08	criteria provided, single submitter	clinical testing	This c.226delA (p.Ile76Tyrfs*101) frameshift variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two unrelated cancer patients (PMID 26681312, 27433846). It is absent in general population databases. Mono-allelic loss of function variants in the PALB2 gene has been associated with susceptibility to breast cancer and pancreatic cancer (PMID: 17200668, 24136930, 25099575). Therefore this c.226delA (p.Ile76Tyrfs*101) variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498645	SCV002807587	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411345	SCV004019666	pathogenic	Familial cancer of breast	2023-03-31	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	RCV000411345	SCV004202630	likely pathogenic	Familial cancer of breast	2023-05-22	criteria provided, single submitter	clinical testing