chr16-23630235-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.1919C>G(p.Ser640Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S640S) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.1919C>G | p.Ser640Ter | stop_gained | 5/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1919C>G | p.Ser640Ter | stop_gained | 5/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 09, 2018 | The PALB2 c.1919C>G; p.Ser640Ter variant, to our knowledge, has not been reported in the medical literature or in gene-specific database. It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, another nucleotide change at this position that results in the same premature termination codon (c.1919C>A; p.Ser640Ter) has been observed in at least one individual affected with early onset breast cancer and is considered pathogenic (Vietri 2015). Based on the above information, the c.1919C>G; p.Ser640Ter variant is considered pathogenic. References: Vietri M et al. Analysis of PALB2 in a cohort of Italian breast cancer patients: identification of a novel PALB2 truncating mutation. Fam Cancer. 2015 Sep;14(3):341-8. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 618260). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25666743). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser640*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 12, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 08, 2020 | The p.S640* pathogenic mutation (also known as c.1919C>G), located in coding exon 5 of the PALB2 gene, results from a C to G substitution at nucleotide position 1919. This changes the amino acid from a serine to a stop codon within coding exon 5. Another alteration at the same codon, p.S640* (c.1919C>A), has been detected in BRCA1/2-negative women with breast cancer (Vietri MT et al, Familial Cancer. 2015 Sep;14:341-8; Hauke J et al, Cancer Med. 2018 04;7:1349-1358). 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