NM_000059.4:c.5986G>A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000059.4(BRCA2):c.5986G>A(p.Ala1996Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,968 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5986G>A | p.Ala1996Thr | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.5617G>A | p.Ala1873Thr | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5986G>A | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000479 AC: 120AN: 250524Hom.: 1 AF XY: 0.000626 AC XY: 85AN XY: 135682
GnomAD4 exome AF: 0.000224 AC: 328AN: 1461716Hom.: 3 Cov.: 45 AF XY: 0.000318 AC XY: 231AN XY: 727160
GnomAD4 genome AF: 0.000112 AC: 17AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74436
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
- -
- -
- -
not provided Benign:4
- -
This variant is associated with the following publications: (PMID: 30093976, 24448499, 22366370, 22752604, 28222693, 28231738, 28301460, 28993434, 31131967, 30055349, 32846166) -
- -
- -
Hereditary cancer-predisposing syndrome Benign:4
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. -
- -
- -
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Hereditary breast ovarian cancer syndrome Uncertain:2Benign:1
- -
- -
- -
not specified Uncertain:1Benign:2
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3 B/LB, 2 VUS; 1 paper in HGMD -
- -
Variant summary: BRCA2 c.5986G>A (p.Ala1996Thr) results in a non-conservative amino acid change located in the BRCA2 repeat domain (IPR002093) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251738 control chromosomes, predominantly at a frequency of 0.0037 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075). c.5986G>A has been reported in the literature in individuals with breast/ovarian cancer or pancreatic cancer (example, Juwle_2012, Kanchi_2014, Levanat_2012, Chan_2018, Darooei_2017, Lai_2017, Santonocito_2020, Wen_2018, Corso_2023, Muhammad_2023, Krivokuca_2022) but also, in healthy controls (e.g. Lai_2017, Wen_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 30093976, 37460658, 28231738, 28301460, 22752604, 24448499, 34284872, 28222693, 22366370, 37951914, 32438681, 28993434). ClinVar contains an entry for this variant (Variation ID: 51982). Based on the evidence outlined above, the variant was classified as likely benign. -
Fanconi anemia complementation group D1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
BRCA2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at