rs1555461765
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5_SupportingPP1_ModeratePVS1PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.514_517del (p.Ser172fs) variant in PALB2 is a frameshift variant predicted to result in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant was found to co-segregate with disease in multiple affected family members in one family (Invitae). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM2_Supporting, PP1_Moderate) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658658444/MONDO:0016419/020
Frequency
Consequence
NM_024675.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Ser172Glyfs*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 variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 461007). For these reasons, this variant has been classified as Pathogenic. -
The c.514_517del (p.Ser172fs) variant in PALB2 is a frameshift variant predicted to result in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant was found to co-segregate with disease in multiple affected family members in one family (Invitae). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM2_Supporting, PP1_Moderate) -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Malignant tumor of breast Pathogenic:1
Variant summary: PALB2 c.514_517delTCTG (p.Ser172GlyfsX4) 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 251460 control chromosomes (gnomAD). c.514_517delTCTG has been reported in the literature in at least one young patient with HER2-amplified breast cancer, a patient with prostate cancer and a breast cancer patient (Eccles_2016, Momozawa_2020, Zhou_2020). These data indicate that the variant may be associated with disease. In a cell based functional assays, compared to wild-type the variant was found to have a relative HR (homologous recombination) efficiency of 8.55% and in PARPi sensitive assays, a PARPi resistance of 13.87% (Boonen_2019). Two other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
This variant deletes 4 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. Based on the available evidence, this variant is classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at