Submissions for variant NM_024675.4(PALB2):c.424A>T (p.Lys142Ter)

gnomAD frequency: 0.00001  dbSNP: rs587782005

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130421	SCV000185284	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-22	criteria provided, single submitter	clinical testing	The p.K142* pathogenic mutation (also known as c.424A>T), located in coding exon 4 of the PALB2 gene, results from an A to T substitution at nucleotide position 424. This changes the amino acid from a lysine to a stop codon within coding exon 4. This mutation was identified in a cohort of breast cancer patients from the UK and was not present in controls (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). 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	RCV000412725	SCV000490683	pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation and 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; This variant is associated with the following publications: (PMID: 28152038, 28779002, 29922827, 26689913, 29625052, 17200672, 17200671, 17200668, 25099575, 35753512, 33471991, 30322717, 24136930, 32885271)
Invitae	RCV000476449	SCV000550632	pathogenic	Familial cancer of breast	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys142*) 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 (rs587782005, gnomAD 0.002%). 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: 141779). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130421	SCV000690930	pathogenic	Hereditary cancer-predisposing syndrome	2017-07-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000476449	SCV000786003	pathogenic	Familial cancer of breast	2018-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001357166	SCV002051215	pathogenic	Malignant tumor of breast	2021-12-17	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.424A>T (p.Lys142X) 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. The variant allele was found at a frequency of 8e-06 in 251270 control chromosomes (gnomAD). c.424A>T has been reported in the literature in individuals affected with breast cancer and ovarian cancer (e.g. Decker_2017, Carter_2018, Huang_2018). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000412725	SCV002506302	pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing	The PALB2 c.424A>T; p.Lys142Ter variant (rs587782005) is reported in the literature in individuals affected with breast or ovarian cancer (Carter 2018, Decker 2017, Huang 2018). This variant is also reported in ClinVar (Variation ID: 141779), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Decker B et al. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 2017 Nov;54(11):732-741. PMID: 28779002. Huang KL et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018 Apr 5;173(2):355-370.e14. PMID: 29625052.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV002251434	SCV002522173	pathogenic	Breast cancer, susceptibility to	2021-08-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130421	SCV002531197	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000476449	SCV004019692	pathogenic	Familial cancer of breast	2023-03-31	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387508	SCV004099121	pathogenic	PALB2-related disorder	2023-09-11	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Baylor Genetics	RCV000476449	SCV004202665	pathogenic	Familial cancer of breast	2023-03-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357166	SCV001552539	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Lys142X variant was not identified in the literature nor was it identified in the COSMIC, MutDB, LOVD 3.0, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs587782005) as “With Pathogenic allele”, and in the ClinVar and Clinvitae databases (3x classified as pathogenic by Ambry Genetics, GeneDx and Invitae). The variant was identified in control databases in 2 of 246078 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 2 of 111646 chromosomes (freq: 0.000018), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The c.424A>T variant leads to a premature stop codon at position 142 which is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.