Submissions for variant NM_024675.4(PALB2):c.487_488del (p.Val163fs)

dbSNP: rs745533713

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255562	SCV000322625	pathogenic	not provided	2021-08-19	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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26556299, 28779002, 29625052, 30303537, 27535533)
Ambry Genetics	RCV000454359	SCV000538176	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-16	criteria provided, single submitter	clinical testing	The c.487_488delGT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 487 to 488, causing a translational frameshift with a predicted alternate stop codon (p.V163Lfs*4). This mutation has been identified in breast cancer patients from multiple cohorts (Schrader KA et al. JAMA Oncol. 2016 Jan;2(1):104-11; Decker B et al. J Med Genet. 2017 Nov;54(11):732-741; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Zanti M et al. Cancers (Basel), 2020 Oct;12; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in a patient with pancreatic cancer (Macklin-Mantia SK et al. Hered Cancer Clin Pract, 2020 Aug;18:17) and a patient with squamous cell carcinoma of the lung (Huang KL et al. Cell, 2018 04;173:355-370.e14). 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.
Color Diagnostics, LLC DBA Color Health	RCV000454359	SCV000686063	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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 more than 10 individuals affected with breast cancer (PMID: 28779002, 33120919, 33471991, 34399810). This variant has been identified in 1/251450 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799725	SCV000939401	pathogenic	Familial cancer of breast	2024-06-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val163Leufs*4) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 265632). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255562	SCV002497896	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272200	SCV002556581	pathogenic	Pancreatic cancer, susceptibility to, 3	2021-02-11	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003389468	SCV004101681	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2023-11-13	criteria provided, single submitter	clinical testing	A known pathogenic variants is detected on the PALB2 gene (c.487_488delGT). This sequence change creates a premature translational stop signal (p.Val163Leufs*4) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 265632). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic variants in the PALB2 cause familial susceptibility to breast-ovarian cancer (OMIM# 620442). This variant has been confirmed by Sanger sequencing.
Myriad Genetics, Inc.	RCV000799725	SCV004188538	pathogenic	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003389468	SCV004231842	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2024-01-18	criteria provided, single submitter	clinical testing