16-23641155-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_024675.4(PALB2):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
PALB2
NM_024675.4 start_lost
NM_024675.4 start_lost
Scores
3
5
8
Clinical Significance
Conservation
PhyloP100: 3.95
Genes affected
PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_024675.4 (PALB2) was described as [Pathogenic] in ClinVar as 1801543
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23641155-C-T is Pathogenic according to our data. Variant chr16-23641155-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23641155-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3G>A | p.Met1? | start_lost | 1/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3G>A | p.Met1? | start_lost | 1/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460610Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726538
GnomAD4 exome
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31
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change affects the initiator methionine of the PALB2 mRNA. The next in-frame methionine is located at codon 296. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with bile duct cancer, breast cancer, glioblastoma multiforme, and/or pancreatic cancer (PMID: 29625052, 31173646, 31263571, 31871297). ClinVar contains an entry for this variant (Variation ID: 371919). If translation initiation is rescued by the downstream methionine at codon 296, this would result in loss of the coiled-coil domain (p.Leu9-Glu42) of the PALB2 protein, which is critical for the interaction between BRCA1/BRCA2, and necessary for homology-directed DNA repair (PMID: 16793542, 19369211, 26649820, 25099575). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Leu35Pro) have been determined to be pathogenic (PMID: 28319063, 30337689, 31586400). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 12, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 30, 2023 | This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 24, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2017 | This variant alters the initiator Methionine codon, and the resultant protein would be described as“p.Met1?†to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein isproduced using an alternate Methionine codon. PALB2 c.3G>A has not been previously published as a pathogenicvariant, nor has it been reported as a benign polymorphism to our knowledge. As PALB2 c.3G>A is predicted to alternormal protein production, it is considered a likely pathogenic variant. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 24, 2023 | The p.M1? variant (also known as c.3G>A) is located in coding exon 1 of the PALB2 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This variant has been reported in an individual with metastatic pancreatic cancer diagnosed at 58 (Goldstein JB et al. Clin Cancer Res. 2020 Mar;26(6):1385-1394). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0925);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at