rs397507637
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.2701delC(p.Ala902LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.2701delC | p.Ala902LeufsTer2 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.2332delC | p.Ala779LeufsTer2 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.2701delC | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1452816Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 721988
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:3
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This variant is denoted BRCA2 c.2701delC at the cDNA level and p.Ala902LeufsX2 (A902LfsX2) at the protein level. The normal sequence with the bases that are deleted in brackets is TAAT[delC]TTGC. The deletion causes a frameshift, changing an Alanine to a Leucine at codon 902, and creating a premature stop codon at position 2 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.2701delC, previously reported as 2929delC (p.L901fsX903), has been seen in association with breast and/or ovarian cancer (Miramar 2008, Beristain 2010) and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). The variant is found in BRCA1-BRCA2 panel(s). -
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Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.2701delC (p.A902Lfs*2) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of one nucleotide at position 2701, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was one of 17 mutations identified in a cohort of Spanish individuals with breast and/or ovarian cancer (Miramar, 2008). This variant was also seen in a 38 year-old male diagnosed with uveal melanoma with four female relatives with breast cancer (Cruz, 2011). This variant was also identified in a cohort of Spanish males with familial breast and ovarian cancer syndrome (de Juan, 2015). Of note, this alteration is also designated as 2929delC, in published literature. Based on the available evidence, this alteration is classified as pathogenic. -
This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 6 individuals affected with breast and/or ovarian cancer (PMID: 18176857, 23479189, 28477318, 28680148, 33471991; Leiden Open Variation Database DB-ID BRCA2_002545) and in families suspected to be affected with hereditary breast and ovarian cancer (PMID: 22460208, 24549055, 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Variant summary: BRCA2 c.2701delC (p.Ala902LeufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 242556 control chromosomes. c.2701delC has been extensively reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and subsequently cited in comprehensive reviews (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Ala902Leufs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with uveal melanoma and colorectal cancer and hereditary breast and ovarian cancer (PMID: 18176857, 22025144, 22460208, 23479189, 24549055, 26026974, 28477318, 28680148). This variant is also known as c.2929delC and p.L901fsX903. ClinVar contains an entry for this variant (Variation ID: 51331). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
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BRCA2-related disorder Other:1
Variant interpreted as Pathogenic and reported on 01-13-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at