13-32337053-A-G
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_000059.4(BRCA2):c.2698A>G(p.Asn900Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,604,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.2698A>G | p.Asn900Asp | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.2329A>G | p.Asn777Asp | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.2698A>G | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000412 AC: 10AN: 242556Hom.: 0 AF XY: 0.0000305 AC XY: 4AN XY: 130982
GnomAD4 exome AF: 0.0000200 AC: 29AN: 1452366Hom.: 0 Cov.: 33 AF XY: 0.0000152 AC XY: 11AN XY: 721748
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74384
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
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IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000293 -
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
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not specified Benign:2
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Variant summary: BRCA2 c.2698A>G (p.Asn900Asp) 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 4.1e-05 in 242556 control chromosomes, predominantly at a frequency of 6.3e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2698A>G, has been reported in the literature in an individuals affected with breast cancer and other tumor phenotypes (examples: Lee_2008 and Zhang_2015), but was also found in healthy controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.68_69delAG (p.Glu23ValfsX17), and BRCA1 c.2722G>T (p.Glu908X); in two internal samples), providing supporting evidence for a benign role. Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=4), while the expert panel classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Hereditary cancer-predisposing syndrome Benign:2
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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. -
Inherited breast cancer and ovarian cancer Benign:1
BP1,BP4,BP5_Strong -
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). -
not provided Benign:1
This variant is associated with the following publications: (PMID: 18284688, 23929434, 20167696, 28843361, 26580448, 31131967) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at