Submissions for variant NM_024675.4(PALB2):c.3004_3007del (p.Glu1002fs)

dbSNP: rs786203488

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166810	SCV000217624	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-04	criteria provided, single submitter	clinical testing	The c.3004_3007delGAAA pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of 4 nucleotides at positions 3004 to 3007, causing a translational frameshift with a predicted alternate stop codon (p.E1002Tfs*4). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635888	SCV000757314	pathogenic	Familial cancer of breast	2023-07-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 187120). This variant is also known as p.E1002Tfs*4. This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 26485759). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1002Thrfs*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).
Color Diagnostics, LLC DBA Color Health	RCV000166810	SCV001348383	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 10 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. To our knowledge, this variant has been reported in an individual affected with prostate cancer (PMID: 26485759). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243834	SCV002512647	likely pathogenic	Fanconi anemia complementation group N	2021-02-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 moderate
Myriad Genetics, Inc.	RCV000635888	SCV004188560	pathogenic	Familial cancer of breast	2023-09-14	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	RCV000635888	SCV004202693	pathogenic	Familial cancer of breast	2022-12-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782275	SCV005395669	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3004_3007delGAAA (p.Glu1002ThrfsX4) 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. The variant was absent in 251436 control chromosomes (gnomAD). c.3004_3007delGAAA has been reported in the literature in individuals affected with breast-, ovarian- and prostate cancer (e.g. Yang_2020, Ruan_2023). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31841383, 37415201). ClinVar contains an entry for this variant (Variation ID: 187120). Based on the evidence outlined above, the variant was classified as pathogenic.