rs587782570
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000261584.9(PALB2):c.2931_2932insA(p.Val978SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L977L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000261584.9 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2931_2932insA | p.Val978SerfsTer2 | frameshift_variant | 9/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2931_2932insA | p.Val978SerfsTer2 | frameshift_variant | 9/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 | |
ENST00000561764.1 | n.420-866dup | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 14, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2023 | This sequence change creates a premature translational stop signal (p.Val978Serfs*2) 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 (rs587782570, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hereditary cancer syndromes (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 142591). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | 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 (gnomAD); This variant is associated with the following publications: (PMID: 31173646, 24763289, 29922827) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 06, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2023 | The c.2931dupA pathogenic mutation, located in coding exon 9 of the PALB2 gene, results from a duplication of A at nucleotide position 2931, causing a translational frameshift with a predicted alternate stop codon. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at