NM_000059.4:c.8057T>C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):āc.8057T>Cā(p.Leu2686Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8057T>C | p.Leu2686Pro | missense_variant | Exon 18 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7688T>C | p.Leu2563Pro | missense_variant | Exon 18 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*115T>C | non_coding_transcript_exon_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*115T>C | 3_prime_UTR_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:3
Variant summary: BRCA2 c.8057T>C (p.Leu2686Pro) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251264 control chromosomes. c.8057T>C has been reported in the literature in one individual affected with Fanconi Anemia and a biallelic BRCA2 genotype (BRCA2 c.9672dupA (paternal) and c.8057T>C (maternal) (Dodgshun_2016). It was also identified in a proband from a family with Hereditary Breast And Ovarian Cancer (Azzollini_2016). At-least two multifactorial probability based assessments have classified this variant with a high probability of pathogenicity (example, Karchin_2008, Lindor_2012). Several publications report consistent experimental evidence evaluating an impact on protein function (example, Guidugli_2018, Hart_2019). The most pronounced variant effect results in defective homology directed repair. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2686 of the BRCA2 protein (p.Leu2686Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 10923033, 26740091). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 52489). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 29988080). For these reasons, this variant has been classified as Pathogenic. -
Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (19.2) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.994 and an overall classification of pathogenic. (PS3_strong). There are two likely pathogenic classifications on ClinVar for this variant from accredited USA diagnostic laboratories (Ambry Genetics and GeneDx, 2016) (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (1), UMD (5), BIC (1), and BRCA2 LOVD (1). -
not provided Pathogenic:2
This variant is denoted BRCA2 c.8057T>C at the cDNA level, p.Leu2686Pro (L2686P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 8285T>C. This variant was observed in an individual diagnosed with Fanconi Anemia who also harbored a pathogenic variant in trans with BRCA2 Leu2686Pro (Dodgshun 2016). This variant was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. BRCA2 Leu2686Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2686Pro occurs at a position that is conserved across species and is located in the DNA binding domain, the nuclear export signal motif, and the SHFM1 binding domain (Marston 1999, Yang 2002, Jayesekharan 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA2 Leu2686Pro to be a likely pathogenic variant. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The p.L2686P pathogenic mutation (also known as c.8057T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8057. The leucine at codon 2686 is replaced by proline, an amino acid with similar properties. This variant was detected in trans with a pathogenic BRCA2 mutation in a patient diagnosed with Fanconi Anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 (Dodgshun AJ. Cancer Genet. 2016;209:53-6). This alteration was defective in homology-directed DNA repair (HDR) assays, as well as a mouse ES cell growth assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med. 2019 02;21:293-302; Hart SN et al. Genet. Med. 2019 01;21:71-80). In addition, in a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted likely deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
This missense variant replaces leucine with proline at codon 2686 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant is deficient in the complementation of BRCA2-deficient mouse embryonic stem cell (PMID: 29988080). This variant has been reported with a pathogenic BRCA2 co-variant in an individual affected with Fanconi anemia with a family history of cancer (PMID: 26740091). This variant was also included in multifactorial analysis studies with discordant reports of pathogenicity (PMID: 21990134, 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at