16-23629645-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_024675.4(PALB2):c.2509G>A(p.Glu837Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. E837Q) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2509G>A | p.Glu837Lys | missense_variant | 5/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2509G>A | p.Glu837Lys | missense_variant | 5/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000998 AC: 25AN: 250516Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135656
GnomAD4 exome AF: 0.000127 AC: 185AN: 1461536Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89AN XY: 727100
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74328
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 15, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | May 01, 2018 | - - |
not specified Uncertain:1Benign:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 26, 2018 | - - |
Benign, no assertion criteria provided | curation | Leiden Open Variation Database | Oct 10, 2018 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2020 | Variant summary: PALB2 c.2509G>A (p.Glu837Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250516 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. Specifically, the variant allele was detected at a frequency of 0.0042 within Korean controls (gnomAD) and at a frequency range of 0.0058-0.0069 within Japanese controls (Momozawa_2018 and HGVD and jMorp databases). Therefore, the observed variant frequency within East Asian control individuals is at least 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Though c.2509G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Nakagomi 2016, Kim 2017, Sato 2017, Shin_2020) and in a patient with Beckwith-Wiedemann syndrome and hepatoblastoma (Kim 2017), these patients were all of East Asian origin. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (BRCA1 c.188T>A, p.L63X; PTEN c.697C>T, p.Arg233X; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2020 | This variant is associated with the following publications: (PMID: 26411315, 29190888, 24728327, 24755471, 27783279, 24163242, 28796317, 29338689) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 24, 2023 | The frequency of this variant in the general population, 0.0042 (16/3818 chromosomes in the Korean subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMIDs: 32019277 (2020), 30287823 (2018)) and colorectal cancer (PMIID: 33309985 (2020)). It has also been reported in a breast cancer association study where the variant was found in individuals with breast cancer as well as in unaffected controls (PMIDs: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Familial cancer of breast Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
PALB2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 09, 2023 | The PALB2 c.2509G>A variant is predicted to result in the amino acid substitution p.Glu837Lys. This variant has been reported in individuals of Asian ancestry with personal and/or family history of breast/ovarian cancer (Nakagomi et al. 2015. PubMed ID: 26411315; Kim et al. 2017. PubMed ID: 27783279; Sato et al. 2017. PubMed ID: 28796317). This variant is reported in 0.11% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23640966-C-T). This variant is present in the ClinVar database with conflicting interpretations of pathogenicity, ranging from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128133/). Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | May 21, 2020 | - - |
Fanconi anemia complementation group N Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Glu837Lys variant was identified in 5 of 780 proband chromosomes (frequency: 0.0064) from individuals or families with breast cancer and was present in 1 of 124 control chromosomes (frequency: 0.008) from healthy individuals (Kim 2017, Nakagomi 2016). The variant was also identified in dbSNP (ID: rs587778587) as “With Pathogenic, other allele”, ClinVar (6x, as likely benign by Invitae, Ilummina, uncertain significance by Ambry Genetics, GeneDx, and ITMI), Clinvitae (4x), Cosmic (1x, large intestine, prostate, carcinoma), databases. The variant was not identified in MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 30 of 276582 chromosomes at a frequency of 0.000108 in the following populations: African in 6 of 25030 chromosomes (freq. 0.00024), East Asian in 24 of 18870 chromosomes (freq. 0.0013), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic BRCA2 variant (c.4042delT, p.Cys1348ValfsX26) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.Glu837Lys variant does not have clinical significance The p.Glu837Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at