rs180177111
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2323C>T(p.Gln775Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q775Q) 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.2323C>T | p.Gln775Ter | stop_gained | 5/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2323C>T | p.Gln775Ter | stop_gained | 5/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251456Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2021 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change creates a premature translational stop signal (p.Gln775*) 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 (rs180177111, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18053174, 19863560, 23302520, 23341105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126646). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 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:3
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 22, 2022 | 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 observed in at least 20 individuals and families affected with breast, ovarian and pancreatic cancer with family history of multiple cancer types (PMID 18053174, 19863560, 23341105, 23302520, 28825143, 30322717, 30720863, 31841383, 33471991; Leiden Open Variation Database DB-ID PALB2_010100). This variant has been identified in 1/251456 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 07, 2023 | The p.Q775* pathogenic mutation (also known as c.2323C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2323. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This alteration has been identified in several breast and/or ovarian cancer families and established as a founder mutation of French-Canadian origin (Foulkes WD et al. Breast Cancer Res. 2007;9(6):R83; Tischkowitz M et al. BMC Med Genet. 2013 Jan;14:5; Wark L et al. Genes Chromosomes Cancer 2013 May;52(5):480-94; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488). This alteration has also been detected in a cohort of Chinese breast cancer patients (Zhang K et al. Breast Cancer Res. Treat., 2017 Dec;166:865-873). 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. - |
Malignant tumor of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 18, 2022 | Variant summary: PALB2 c.2323C>T (p.Gln775X) 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 4e-06 in 251456 control chromosomes (gnomAD). c.2323C>T has been reported in the literature in multiple individuals affected with Breast Cancer (e.g. Tischkowitz_2013, Yang_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Pauty_2017). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Gln775* variant was identified in 6 of 1936 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and was not identified in 24880 chromosomes from healthy controls (Foulkes 2007, Tischkowitz 2013, Catucci 2016). The variant was also identified in dbSNP (ID: rs180177111) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters), LOVD 3.0 (7x), and in Zhejiang University Database (1x). The variant was not identified in the Cosmic database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln775* variant leads to a premature stop codon at position 775, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 assosiated cancers and is the type of variant expected to cause the disorder. The variant has been found to recur in French Canadian HBC families and breast cancer cases and is considered a founder mutation in the French Canadian population (Arcand 2015). In a structure–function analysis of PALB2 the variant was able to bind the same DNA substrates as wild-type PALB2 (wt) but with some differences in affinity; it displayed reduced affinity for the D-loop and ability to form foci in the nucleus (Pauty 2017). In addition, mean fluorescent intensity was significantly increased and reduced telomeric signals were observed in cells carrying the PALB2 c.2323C>T variant which were generated from patient-derived cell lines (Wark 2013). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2022 | 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); This variant is associated with the following publications: (PMID: 25525159, 30322717, 32885271, 18053174, 28158555, 19863560, 24485656, 31841383, 28825143, 28888541, 31784482, 29922827, 34861889, 26137147, 32339256, 23341105, 25099575, 23302520, 21947752, 30720863, 32300229, 27624329) - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Breast cancer, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at