rs1555460542

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024675.4(PALB2):​c.1972G>T​(p.Glu658Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

PALB2
NM_024675.4 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.36
Variant links:
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 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23630182-C-A is Pathogenic according to our data. Variant chr16-23630182-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 830154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630182-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALB2NM_024675.4 linkuse as main transcriptc.1972G>T p.Glu658Ter stop_gained 5/13 ENST00000261584.9 NP_078951.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkuse as main transcriptc.1972G>T p.Glu658Ter stop_gained 5/131 NM_024675.4 ENSP00000261584 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 14, 2024This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseMay 13, 2019Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 03, 2022This sequence change creates a premature translational stop signal (p.Glu658*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 830154). This premature translational stop signal has been observed in individual(s) with personal and/or family history of hereditary breast and ovarian cancer (PMID: 24549055). This variant is not present in population databases (gnomAD no frequency). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2023The p.E658* pathogenic mutation (also known as c.1972G>T), located in coding exon 5 of the PALB2 gene, results from a G to T substitution at nucleotide position 1972. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This variant was identified in a cohort of 767 high-risk breast and/or ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). This variant is considered to be rare based on population 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Uncertain
0.20
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.40
N
MutationTaster
Benign
1.0
A
Vest4
0.68
GERP RS
2.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555460542; hg19: chr16-23641503; COSMIC: COSV55167770; API