16-23629818-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2336C>G(p.Ser779*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 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
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251436Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135900
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Ser779*) 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 (rs764509489, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 30303537, 31206626). ClinVar contains an entry for this variant (Variation ID: 186458). For these reasons, this variant has been classified as Pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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); Observed in individuals with PALB2-related cancers (Girard et al., 2019; Weitzel et al., 2019; Doddato et al., 2021); This variant is associated with the following publications: (PMID: 29922827, 31206626, 30303537, 34026625, 33811135) -
The PALB2 c.2336C>G (p.Ser779*) variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with breast/ovarian cancer (PMIDs: 35610400 (2022), 34026625 (2021), 31206626 (2019), 30303537 (2019)). The frequency of this variant in the general population, 0.000087 (3/34578 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 5 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in five individuals affected with breast cancer (PMID: 30303537, 31206626, 33811135, 34026625) and also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010910). This variant has been identified in 3/251436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The p.S779* pathogenic mutation (also known as c.2336C>G), located in coding exon 5 of the PALB2 gene, results from a C to G substitution at nucleotide position 2336. This changes the amino acid from a serine to a stop codon within coding exon 5. This alteration has been detected in multiple breast cancer patients and families (Girard E et al. Int J Cancer, 2019 Apr;144:1962-1974; Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Ng PS et al. J Med Genet, 2022 May;59:481-491; Doddato G et al. Front Oncol, 2021 May;11:649435). 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. -
PALB2-related disorder Pathogenic:1
The PALB2 c.2336C>G variant is predicted to result in premature protein termination (p.Ser779*). This variant was reported in multiple individuals with breast cancer (Table S2, Weitzel et al. 2019. PubMed ID: 31206626; Table S3, Girard et al. 2019. PubMed ID: 30303537; Doddato et al. 2021. PubMed ID: 34026625). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641139-G-C) and is listed in ClinVar with interpretations of likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/186458/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Variant summary: PALB2 c.2336C>G (p.Ser779X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251436 control chromosomes (gnomAD). c.2336C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (examples: Weitzel_2019, Doddato_2021, and Gonzalez_2022). These data indicate that the variant is likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=5)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at