rs367578415
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The NM_024675.4(PALB2):c.1189A>T(p.Thr397Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,613,936 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T397A) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.1189A>T | p.Thr397Ser | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1189A>T | p.Thr397Ser | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250934Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135616
GnomAD4 exome AF: 0.0000670 AC: 98AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727144
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 397 of the PALB2 protein (p.Thr397Ser). This variant is present in population databases (rs367578415, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and pancreatic cancer (PMID: 17200668, 26283626, 26483394). ClinVar contains an entry for this variant (Variation ID: 142048). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 17, 2017 | - - |
Likely benign, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Apr 20, 2022 | The PALB2 c.1189A>T (p.Thr397Ser) missense change has a maximum subpopulation frequency of 0.0039% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in individuals with breast (PMID: 17200668, 26283626), pancreatic (PMID: 26483394), and ovarian cancers (PMID: 32546565), as well as in control individuals (PMID: 17200668, 26283626). It is reported to be in one woman older than 70 years of age without cancer (FLOSSIES database, https://whi.color.com/). A functional study demonstrates that this variant has homology directed repair activity similar to the wild-type (BS3; PMID: 31636395). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2023 | Variant summary: PALB2 c.1189A>T (p.Thr397Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 257098 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1189A>T has been reported in the literature in individuals affected with breast cancer and pancreatic cancer (e.g. Rahman_2007, Thompson_2015, Hu_2015, Decker_2017) but also in healthy control individuals (e.g. Rahman_2007, Thompson_2015, Decker_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homology directed DNA repair versus the WT protein (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 17200668, 26283626, 31636395, 28779002). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as uncertain significance and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This missense variant replaces threonine with serine at codon 397 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not affect homology-directed repair activity of the PALB2 protein (PMID: 31636395). This variant has been reported in an individual affected with pancreatic cancer (PMID: 26483394) and in a breast cancer case-control meta-analysis in 8/60466 cases and 5/53461 unaffected individuals (PMID:3347191; Leiden Open Variation Database DB-ID PALB2_010819). This variant has been identified in 5/282346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The p.T397S variant (also known as c.1189A>T), located in coding exon 4 of the PALB2 gene, results from an A to T substitution at nucleotide position 1189. The threonine at codon 397 is replaced by serine, an amino acid with similar properties. This alteration has been reported in breast and pancreatic cancer patients as well as in a cancer-free control (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11; Decker B et al. J Med Genet, 2017 11;54:732-741). A functional analysis assessing the impact of missense alterations in the PALB2 chromatin association motif (ChAM) demonstrated that this alteration does not appear to impair or hinder chromatin association (Bleuyard JY et al. Wellcome Open Res. 2017 Nov 14;2:110). This alteration was also found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 03;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 05, 2022 | - - |
Inherited breast cancer and ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | May 10, 2024 | BP1 - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: homology directed repair activity similar to wild-type (Wiltshire et al., 2019); Observed in individuals with breast and pancreatic cancer, but also in control populations (Rahman et al., 2007; Hu et al., 2015; Thompson et al., 2015; Decker et al., 2017); This variant is associated with the following publications: (PMID: 26483394, 17200668, 26283626, 29387807, 28779002, 31636395, 22193777) - |
Familial ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at