rs1060502788
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.1048C>T(p.Gln350*) 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
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 Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This variant is denoted PALB2 c.1048C>T at the cDNA level and p.Gln350Ter (Q350X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported in at least one women with a history of bilateral breast cancer (Kim 2016) and isconsidered pathogenic -
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
This sequence change creates a premature translational stop signal (p.Gln350*) 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: 27783279). ClinVar contains an entry for this variant (Variation ID: 410191). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.Q350* pathogenic mutation (also known as c.1048C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 1048. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration was identified in an individual with bilateral breast cancer in a study of 235 Korean individuals with a personal or family history suggestive of hereditary breast cancer (Kim H et al. Breast Cancer Res. Treat., 2017 01;161:95-102). This alteration has also been reported in 3/7051 unselected breast cancer patients and in 0/11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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