rs515726108
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_024675.4(PALB2):c.315G>C(p.Glu105Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. E105Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.315G>C | p.Glu105Asp | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.315G>C | p.Glu105Asp | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152010Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251116Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135698
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727100
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152010Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74232
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 28, 2023 | This missense variant replaces glutamic acid with aspartic acid at codon 105 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast and/or ovarian cancer (PMID: 22241545, 30651582) and in an individual affected with childhood-onset leukemia (PMID: 31721781). This variant also has been reported in several cancer case-control studies. In two breast cancer case-control studies, this variant has been detected in 7/7051 female breast cancer cases and 5/11241 unaffected controls (PMID: 30287823) and in 4/60466 cancer cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010032). This variant has been detected in 2/1005 pancreatic cancer cases and 6/23705 unaffected individuals (PMID: 32980694) and 2/7636 prostate cancer cases and 1/12366 unaffected individuals (PMID: 31214711). This variant has been identified in 7/282494 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. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2023 | The p.E105D variant (also known as c.315G>C), located in coding exon 4 of the PALB2 gene, results from a G to C substitution at nucleotide position 315. The glutamic acid at codon 105 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported in multiple unique cohorts of breast and/or ovarian cancer patients, but has also been reported in healthy control populations (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80; Decker B et al. J Med Genet, 2017 11;54:732-741; Momozawa Y et al. Nat Commun. 2018 10;9:4083; Krivokuca A et al. J Hum Genet, 2019 Apr;64:281-290). This amino acid position is not well 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 24, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 21, 2017 | - - |
not provided Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | PALB2: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Dec 30, 2022 | PM2_SUP, BP4 - |
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke, Yukihide Momozawa. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, one of whom also had ovarian cancer but harbored a BRCA1 pathogenic variant, pancreatic cancer, and in unaffected controls (Tischkowitz 2012, Decker 2017, Momozawa 2018, Krivokuca 2019, Mizukami 2020); This variant is associated with the following publications: (PMID: 32980694, 30651582, 28779002, 30404791, 30287823, 22241545) - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2024 | Variant summary: PALB2 c.315G>C (p.Glu105Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.315G>C has been reported in the literature in individuals affected with Breast Cancer (e.g., Tischkowitz_2012, Krivokuca_2019), pancreatic cancer (e.g., Mizukami_2020), and ovarian cancer (e.g., Prokofyeva_2023, Krivokuca_2019). Additionally one Japanese case-control association study on 7,051 unselected breast cancer cases and 11,241 female controls showed no association of this variant with breast cancer along with a final assessment as benign (Momozawa_2018); conversely, another Japanese case-control study on 1,005 pancreatic cancer patients and 23,705 controls reported the variant with an odds ratio of 7.9 (95% CI: 0.8-44.1; Mizukami_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2-associated cancers. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.1054G>T, p.Glu352*) in a 46 year old with HBOC and a family history of breast cancer, providing supporting evidence for a benign role (Krivocuca_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30651582, 30287823, 22241545, 37013556, 28779002, 32980694). ClinVar contains an entry for this variant (Variation ID: 126718). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
PALB2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 12, 2024 | The PALB2 c.315G>C variant is predicted to result in the amino acid substitution p.Glu105Asp. This variant was reported in individuals with breast, ovarian, pancreatic, or biliary tract cancers; however, this variant was also documented in control individuals (supplementary data 1, Momozawa et al. 2018. PubMed ID: 30287823; Table S6, Mizukami et al. 2020. PubMed ID: 32980694; Table S2, Okawa et al. 2023. PubMed ID: 36243179; Prokofyeva et al. 2023. PubMed ID: 37013556). This variant was also documented in an individual from a hereditary breast and ovarian cancer (HBOC) cohort; however, this individual also carried a nonsense BRCA1 variant (subject #ID347 in Table A.1 and Table A.2, Krivokuca et al. 2022. PubMed ID: 34284872). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126718/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the PALB2 protein (p.Glu105Asp). This variant is present in population databases (rs515726108, gnomAD 0.005%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22241545, 30287823, 30651582, 34284872). ClinVar contains an entry for this variant (Variation ID: 126718). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at