13-32362595-G-C
Variant summary
Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.7878G>C(p.Trp2626Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 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 Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2626R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 22 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.7878G>C | p.Trp2626Cys | missense_variant | Exon 17 of 27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.7878G>C | p.Trp2626Cys | missense_variant | Exon 17 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.7509G>C | p.Trp2503Cys | missense_variant | Exon 17 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.7886G>C | non_coding_transcript_exon_variant | Exon 16 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251276 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727226 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10Uncertain:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
PS3; PP3; PM1; Expert panel
Criteria applied: PS3,PP4_STR,PM3,PM2_SUP,PP3
not provided Pathogenic:10
Multifactorial studies suggest this variant is associated with breast and ovarian cancer, but may confer lower risks than typical BRCA2 pathogenic variants (Biswas et al., 2011; Lindor et al., 2012; Pruss et al., 2014; Li et al., 2020; Li et al., 2022); Published functional studies demonstrate a damaging effect: impaired homologous recombination and sensitivity to PARP inhibitors (Biswas et al., 2011; Stoepker et al., 2015; Guidugli et al., 2018; Ikegami et al., 2020; Lee et al., 2021; Iversen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 8106G>C; This variant is associated with the following publications: (PMID: 23108138, 17924331, 22666503, 20104584, 27194814, 29478780, 31409081, 29446198, 30291343, 12228710, 25146914, 25583207, 16115142, 21719596, 19043619, 24323938, 21520273, 25085752, 16825431, 18951461, 25782689, 27767231, 28315974, 21138478, 26566862, 28866612, 21203900, 21990165, 29339979, 28541631, 30257646, 30728895, 29988080, 30720243, 31853058, 30696104, 32444794, 29884841, 31263571, 30702160, 31825140, 32719484, 29625052, 32885271, 32853339, 30787465, 32295079, 34906479, 34680878, 29394989, 21990134, 15070707, 29922827, 31794323, 35665744, 33978741, 34308104)
The frequency of this variant in the general population, 0.000008 (2/251276 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant is described as a pathogenic variant with reduced penetrance, carrying a lower breast cancer risk than other BRCA2 pathogenic variants (PMID: 34906479 (2022)). It has been reported in individuals or families with breast cancer (PMIDs: 34680878 (2021), 34906479 (2022), 30728895 (2019), 30257646 (2018), 29339979 (2018), 27194814 (2016), 26014432 (2015), 22666503 (2012), 21203900 (2011)) or prostate cancer (PMID: 32853339 (2021)). This variant has also been reported in trans with a second pathogenic BRCA2 variant in patients with Fanconi anemia (PMIDs: 21138478 (2011), 15070707 (2004)). Published functional studies indicate that this variant impairs BRCA2 protein activity (PMIDs: 33978741 (2021), 32444794 (2020), 30696104 (2019), 29884841 (2019), 29394989 (2018), 29988080 (2018), 25146914 (2014), 23108138 (2013), 21719596 (2011)). Based on the available information, this variant is classified as pathogenic with reduced penetrance.
PP4_strong, PM3_strong, PS3
BRCA2: PS3, PM1, PS4:Moderate, PM2:Supporting, PP3
The BRCA2 c.7878G>C; p.Trp2626Cys variant (rs80359013, ClinVar Variation ID: 38125), is reported in the literature in multiple individuals with hereditary breast and ovarian cancer, Fanconi anemia D1, or triple-negative breast cancer (Barber 2005, Heramb 2018, Meyer 2012, Winter 2016). Functional analyses of the variant protein show this variant causes a decrease in BRCA2 protein function (Biswas 2011, Guidugli 2014, Ikegami 2020, Mesman 2019). Furthermore, this variant is reported to have an odds ratio favoring causality of 48:1 based on family history, co-occurrence, and co-segregation data (Easton 2007, Guidugli 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.002% (2/113,590 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.7876T>C; p.Trp2626Arg) has been reported in individuals with breast cancer and is considered pathogenic (Han 2006). Computational analyses predict that this variant is deleterious (REVEL: 0.908). Based on available information, this variant is considered to be pathogenic. References: Barber LM et al. Inherited FANCD1/BRCA2 exon 7 splice mutations associated with acute myeloid leukaemia in Fanconi anaemia D1 are not found in sporadic childhood leukaemia. Br J Haematol. 2005 Sep;130(5):796-7. PMID: 16115142. Biswas K et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood. 2011 Sep 1;118(9):2430-42. PMID: 21719596. Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. PMID: 23108138. Guidugli L et al. Functional assays for analysis of variants of uncertain significance in BRCA2. Hum Mutat. 2014 Feb;35(2):151-64. PMID: 24323938. Han SH et al. Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer. Clin Genet. 2006 Dec;70(6):496-501. PMID: 17100994. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Ikegami M et al. High-throughput functional evaluation of BRCA2 variants of unknown significance. Nat Commun. 2020 May 22;11(1):2573. PMID: 32444794. Mesman RLS et al. The functional impact of variants of uncertain significance in BRCA2. Genet Med. 2019 Feb;21(2):293-302. PMID: 29988080. Meyer P et al. BRCA2 mutations and triple-negative breast cancer. PLoS One. 2012;7(5):e38361. PMID: 22666503. Winter C et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann Oncol. 2016 Aug;27(8):1532-8. PMID: 27194814.
Hereditary breast ovarian cancer syndrome Pathogenic:5
According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:29988080, 29884841, 32444794), PM3 (medium pathogenic): Kopic et al. 2011, PMID: 21138478 & Wagner et al. 2004, PMID: 15070707 (3pt), PP3 (supporting pathogenic): BayesDel no AF: 0,48, PP4 (strong pathogenic): Combined LR Score (USCS): 48.97788, BS4 (strong benign): Reduced Penetrance???
This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 2626 of the BRCA2 protein (p.Trp2626Cys). This variant is present in population databases (rs80359013, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and Fanconi anemia (PMID: 11802209, 15070707, 16115142, 20104584, 21138478, 21203900, 22666503, 25085752). 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: 38125). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 17924331, 21719596, 21990134, 23108138, 25146914). For these reasons, this variant has been classified as Pathogenic.
The p.Trp2626Cys variant in BRCA2 has been reported in >16 individuals with BRCA 2-associated cancers (Han 2006, Petersen 2016, Breast Cancer Information Core). This variant has been identified in 2/66726 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359013) . However, this frequency is low enough to be consistent with the frequency of h ereditary breast and ovarian cancer (HBOC) in the general population. In vitro f unctional studies provide some evidence that the p.Trp2626Cys may impact protein function (Hendriks 2014). Computational prediction tools and conservation analy sis suggest that the p.Trp2626Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In addition, this variant was classified as Pathogenic on Aug 10, 2016 by the ClinGen-approved EN IGMA expert panel (ClinVar SCV000244475.1). In summary, although additional stud ies are required to fully establish its clinical significance, the p.Trp2626Cys variant is likely pathogenic.
BRCA2 c.7878G>C (p.Trp2626Cys) results in a non-conservative amino acid change in the helical domain (IPR015252). Five in-silico tools predict a damaging effect. Observed at a frequency of 7.9e-06 in 251676 control chromosomes. Reported in individuals with Hereditary Breast and Ovarian Cancer (PMID's listed) and in trans with another BRCA2 variant (2041insA) in individuals with Fanconi Anemia (PMID's listed and BIC database). Several publications report experimental evidence demonstrating an inability to complement the cell lethal phenotype induced by loss of endogenous mouse BRCA2 (PMID's listed). One expert panel (ENIGMA) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=6)/likely pathogenic (n=5). Based on the evidence outlined above, the variant was re-classified as pathogenic.
This sequence change replaces Tryptophan with Cysteine at codon 2626 of the BRCA2 protein. The tryptophan residue is highly conserved among species in a domain of the protein that is known to be functionally important. There is a large physiochemical difference between tryptophan and cysteine(Grantham Score 215). This variant is listed in population databases at a very low frequency (rs80359013, ExAC <0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID:22666503, 21203900, 20104584, 25085752, 11802209) and in patients affected with Fanconi anemia on the opposite chromosome of a second pathogenic BRCA2 variant (PMID:16115142, 15070707, 21138478).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein.Moreover, experimental studies have shown that the complementation capability of this variant is absent or partially retained in BRCA2-deficient mouse-embryonic stem cells (PMID:21719596, 25146914) and this variant affects sensitivity to DNA damaging agents as well as homology-directed repair activity (PMID:21719596, 23108138).Based on the classification criteria set by the ACMG and AMP (PMID:25741868) this variant has been classified as pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.W2626C pathogenic mutation (also known as c.7878G>C), located in coding exon 16 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7878. The tryptophan at codon 2626 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been described in families with phenotypes consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Meindl A et al. Int. J. Cancer 2002 Feb;97:472-80; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Konecny M et al. Breast Cancer Res. Treat. 2011 Feb;126:119-30; Meyer P et al. PLoS ONE 2012;7:e38361; Winter C et al. Ann. Oncol. 2016 Aug;27:1532-8; Polsler L et al. Eur. J. Hum. Genet. 2016 Feb;24:258-62). This variant has also been identified in two unrelated patients with Fanconi Anemia (Wagner JE et al. Blood. 2004 Apr;103:3226-9; Kopic S et al. Acta Paediatr. 2011 May;100:780-3). In one of these patients, this alteration was confirmed to be in trans with a frameshift mutation (Wagner JE et al. Blood. 2004 Apr;103:3226-9). Functional assays evaluating homology-directed DNA break repair (HDR), embryonic stem cell rescue viability, susceptibility to DNA damaging agents, chromosomal aberration, and RAD51 foci have all indicated deficient function in BRCA2 p.W2626C mutants (Biswas K et al. Blood. 2011 Sep;118:2430-42; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Hendriks G et al. Hum. Mutat. 2014 Nov;35:1382-91; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med., 2018 Jul;). However, one paper describes this as a hypomorphic variant based on a history weighting algorithm (Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). 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 majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
This missense variant replaces tryptophan with cysteine at codon 2626 in the DNA binding of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant showed loss of function in homology-directed repair and DNA damage response assays, a haploid cell proliferation assay and the complementation of Brca2-deficient mouse embryonic stem cells, and it impaired nuclear localization of BRCA2 protein (PMID: 21719596, 23108138, 25146914, 29884841, 29988080, 33978741, 39779857). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11802209, 20104584, 21203900, 22666503, 26014432, 27194814) and this variant also has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000238). In a study of 34 families, this variant has shown reduced penetrance and lower risk of breast cancer compared with other pathogenic variants in the BRCA1 and BRCA2 genes (PMID: 34906479). This variant has also been observed in two unrelated, biallelic individuals affected with Fanconi anemia, who were compound heterozygous with pathogenic variant in the same gene (PMID: 15070707; 16115142, 21138478), indicating that this variant contribute to disease. This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance.
Familial cancer of breast Pathogenic:2
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Criteria applied: PS3, PM3_SUP, PP1_STR, PM2_SUP, PP3
Breast and/or ovarian cancer Pathogenic:1
BRCA2-related cancer predisposition Pathogenic:1
This missense variant replaces tryptophan with cysteine at codon 2626 in the DNA binding 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). Functional studies have shown that this variant showed loss of function in homology-directed repair and DNA damage response assays and the complementation of Brca2-deficient mouse embryonic stem cells, and it impaired nuclear localization of BRCA2 protein (PMID: 21719596, 23108138, 25146914, 29884841, 29988080, 33978741). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11802209, 20104584, 21203900, 22666503, 26014432, 27194814) and this variant also has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000238). In a study of 34 families, this variant has shown reduced penetrance and lower risk of breast cancer compared with other pathogenic variants in the BRCA1 and BRCA2 genes (PMID: 34906479). This variant has also been observed in two unrelated, biallelic individuals affected with Fanconi anemia, who were compound heterozygous with pathogenic variant in the same gene (PMID: 15070707; 16115142, 21138478), indicating that this variant contribute to disease. This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance.
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Trp2626Cys variant was identified in 4 of 7208 proband chromosomes (frequency: 0.0006) from individuals or families with contralateral and unilateral breast cancers, and was not identified in 2996 control chromosomes from healthy individuals (Borg 2010 PMID:20104584, Pruss 2014 PMID:25085752, Capanu 2011 PMID:21520273, Petersen 2016 PMID:26733283). The variant has also been identified in at least one patient with Fanconi anemia who also harboured a BRCA2 frameshift pathogenic variant (Stoepker 2015 PMID:25583207). In a study done to classify unknown variants, the variant was submitted to web-based algorithms using Align-GVGD, Grantham Variation and Grantham Deviation scores and found to be class (C65) of substitutions, which is most likely to interfere with function and was scored as possibly deleterious (Borg 2010 PMID:20104584). Furthermore studies classified the variant as deleterious based on a loss of DNA repair function identified through function studies (Biswas 2011 PMID:21719596, Guidugli 2013 PMID: 23108138, Hendriks 2014 PMID:25146914). The variant was shown to be sensitive to PARP inhibitors when present in a cell line derived from a patient with Fanconi anemia (Stoepker 2015). In addition Lindor et al. 2011 (PMID:21990134) determined the variant to be pathogenic (48.14 possibility of causality) when they weighted together segregation data, co-occurrence with pathogenic variants, personal and family history, and tumor pathology. However the above study by Biswas et al. 2011 demonstrated that the variant may be hypomorphic as it was able to recuse lethality in embryonic stem cells (notably in a similar experiment in the Hendrick et al. study the variant did not rescue lethality), and Pruss et al. 2014 also classified the variant as hypomorphic based on clinic history weighting algorithm. The variant was identified in dbSNP (ID: rs80359013 “With Pathogenic Allele”, in 1000 Genomes Project in 2 of 100000 chromosomes (frequency: 0.00002). The variant was also identified in the Exome Aggregation Consortium database (released Mar 14, 2016) in 2 of 121350 chromosomes (frequency: 0.00002) from a population of 2 of 66726 (0.00003) of European (Non-Finnish) alleles, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in GeneInsight-COGR by Trillum Health Partners 1x as Class 5, in Clinvar (pathogenic by ENIGMA, Quest, CIMBA, Counsyl, LMM, and Invitae, AND as likely pathogenic by LabCorp, GeneDx, Oslo University, Ambry, SCRP, and Medical University Innsbruck as well as Uncertain Significance by BIC). The variant is further identified in the BIC database 14X with unknown clinical importance, in the ARUP Laboratories BRCA Mutations Database 1x as definitely pathogenic, in the Fanconi Anemia Mutation Database (LOVD) 2x as predicted deleterious and 1x with reduced complementation. The variant was not listed in the COSMIC, MutDB, and UMD databases. The p.Trp2626 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 pathogenic role for this variant. This variant is classified as likely pathogenic.
Uterine corpus cancer Pathogenic:1
Computational scores
Source:
Splicing
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