Submissions for variant NM_024675.4(PALB2):c.1451T>A (p.Leu484Ter)

dbSNP: rs786203714

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167136	SCV000217966	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-26	criteria provided, single submitter	clinical testing	The p.L484* pathogenic mutation (also known as c.1451T>A), located in coding exon 4 of the PALB2 gene, results from a T to A substitution at nucleotide position 1451. This changes the amino acid from a leucine to a stop codon within coding exon 4. This variant has been reported in multiple individuals with breast cancer (Yadav S et al. Fam Cancer. 2017 07;16:319-328; Decker B et al. J Med Genet. 2017 11;54:732-741; Liu X et al. Cancer Med. 2017 03;6:547-554; Zhou J et al. Cancer. 2020 Jul;126:3202-3208; Kaneyasu T et al. NPJ Breast Cancer. 2020 Jun;6:25). This variant was not reported in population-based 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587378	SCV000699534	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-16	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.1451T>A (p.Leu484X) variant results in a premature termination codon, predicted to cause a truncated or absent PALB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in breast cancer patients (HGMD: p.S524*, p.E545*, p.W906*, p.Y1183*, etc.), however this particular variant has not been cited in the literature. One in silico tool predicts a damaging outcome for this variant. This variant was absent in 121372 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310142	SCV001499702	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001310142	SCV001584876	pathogenic	Familial cancer of breast	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu484*) 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: 28135048, 28423363, 28779002). ClinVar contains an entry for this variant (Variation ID: 187412). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001543564	SCV001762225	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167136	SCV002051915	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with breast cancer (PMID: 27878467, 28779002, 32339256, 33471991; Leiden Open Variation Database DB-ID PALB2_011031). This variant has not been identified 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.
GeneDx	RCV001543564	SCV002558483	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Nonsense 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: 28423363, 28135048, 32339256, 32885271, 34299313, 28779002)
Genetics and Molecular Pathology, SA Pathology	RCV001310142	SCV002761702	pathogenic	Familial cancer of breast	2020-04-15	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001310142	SCV002762830	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR, PM2_SUP
Myriad Genetics, Inc.	RCV001310142	SCV004189482	pathogenic	Familial cancer of breast	2023-09-08	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.
Baylor Genetics	RCV001310142	SCV004202020	pathogenic	Familial cancer of breast	2023-10-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414940	SCV000492627	pathogenic	Generalized hypopigmentation; Basal cell carcinoma	2016-03-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356904	SCV001552190	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu484* variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs786203714) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Ambry Genetics and one other clinical laboratory; and classified as likely pathogenic by Integrated Genetics/Laboratory Corporation of America). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Leu484* variant leads to a premature stop codon at position 484, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2-associated cancers and this 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.