16-23636043-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.503C>A(p.Ser168*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:4
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
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This sequence change creates a premature translational stop signal (p.Ser168*) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21618343). ClinVar contains an entry for this variant (Variation ID: 126754). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Nonsense 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21618343, 33471991, 25525159, 27191893, 24870022, 32546565, 22692731) -
The PALB2 c.503C>A (p.Ser168*) variant causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMIDs: 21618343 (2011) and 31619740 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.S168* pathogenic mutation (also known as c.503C>A), located in coding exon 4 of the PALB2 gene, results from a C to A substitution at nucleotide position 503. This changes the amino acid from a serine to a stop codon within coding exon 4. This mutation was reported in a patient with a personal history of hormone receptor negative breast cancer diagnosed at age 39 and a family history of breast cancer (Hellebrand H et al. Hum. Mutat. 2011 Jun;32:E2176-88). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at