NM_000059.4:c.9720T>C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000059.4(BRCA2):c.9720T>C(p.Val3240Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_000059.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 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.9720T>C | p.Val3240Val | synonymous_variant | Exon 27 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9351T>C | p.Val3117Val | synonymous_variant | Exon 27 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1778T>C | non_coding_transcript_exon_variant | Exon 26 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1778T>C | 3_prime_UTR_variant | Exon 26 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.000420 AC: 64AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000916 AC: 23AN: 251096Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135730
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461572Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727086
GnomAD4 genome AF: 0.000420 AC: 64AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Variant summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC with an allele frequency of 10/121302 (1/12195), predominantly found in the African cohort, 10/10370 (1/1037), which exceeds the maximum expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Therefore, suggesting that the variant of interest is a rare polymorphism specific to population(s) of African origin. The variant of interest has been reported in at least one affected individual via a publication, although with limited information (ie lack co-segregation data). However, an internal LCA sample reports the variant to co-occur with another probable pathogenic BRCA2 variant, c.2480dupA (p.N827fsX3 classified as likely pathogenic). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign. -
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not specified Benign:4
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:2
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Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
Hereditary cancer-predisposing syndrome Benign:3
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. -
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Hereditary breast ovarian cancer syndrome Benign:2
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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). -
Malignant tumor of breast Benign:1
The BRCA2 p.Val3240Val variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was not identified in the literature, but was identified in the BIC database (5X as a variant with unknown clinical importance), and in dbSNP (ID: rs80359810) “With untested allele”. The variant was identified in the NHLBI Exome Sequencing Project (Exome Variant Server) in 10 of 4406 African American chromosomes (frequency: 0.002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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 predicted benign. -
Familial cancer of breast Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at