Submissions for variant NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe)

dbSNP: rs80359014

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV000077415	SCV004101436	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-08	reviewed by expert panel	curation	The c.7879A>T variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 2627 (p.Ile2627Phe). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.25 indicating that impact on BRCA2 function via protein change is unclear (score range 0.18-0.30). SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (no bioinformatic code is applied). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 29988080, 33609447, 32444794) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 406 (based on Cosegregation LR=1.88; Co-occurrence LR=1.28; Family History LR=168.6), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 17924331). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP4_Very strong, PS3).
Invitae	RCV000045337	SCV000073350	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2627 of the BRCA2 protein (p.Ile2627Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer and prostate cancer (PMID: 10699917, 20104584, 20383589, 21232165, 25452441, 29335924, 29368341). This variant is also known as 8107A>T. ClinVar contains an entry for this variant (Variation ID: 52430). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 18451181, 23108138, 25146914, 29394989, 29884841). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131675	SCV000186711	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The p.I2627F variant (also known as c.7879A>T), located in coding exon 16 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7879. The isoleucine at codon 2627 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat. 2012;33(1):8-21; Hendriks G et al. Hum. Mutat. 2014;35(11):1382-91). In multiple studies, this alteration was detected in several individuals with breast or ovarian cancer (Spitzer E et al. Int. J. Cancer 2000;85(4):474-81; Balabas A et al. Fam. Cancer 2010;9(3):267-74; Stegel V et al. BMC Med. Genet. 2011;12():9; Kluska A et al. BMC Med Genomics 2015;8():19; Couch FJ et al. J. Clin. Oncol. 2015;33(4):304-11; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zakrzewski F et al. BMC Cancer 2019 Apr;19(1):396). This alteration was identified in 1/150 unselected patients with recurrent or metastatic prostate cancer (Isaacsson Velho P et al. Prostate 2018 04;78:401-407). A homology-directed DNA repair (HDR) assay demonstrated p.I2627F to have low functionality, with a probability of pathogenicity of 0.990 (Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102(2):233-248). In another study, this variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet Med. 2019 01;21:71-80). In addition, a mouse embryonic stem cell assay showed that p.I2627F was unable to complement Brca2-deficient cell lethal phenotype (Mesman R et al. Genet. Med. 2019 02;21(2):293-302). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077415	SCV000267813	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000218666	SCV000278877	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced homology directed repair activity and an increase in centriole amplification when compared to wild-type (Farrugia 2008, Guidugli 2013, Guidugli 2018); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Observed in individuals with BRCA2-related cancers (Spitzer 2000, Balabas 2010, Stegel 2011, Lee 2014, Meisel 2017, Jakimovska 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8107A>T; This variant is associated with the following publications: (PMID: 29368341, 29394989, 25447315, 22430266, 19043619, 21232165, 25452441, 21520273, 24323938, 25146914, 17924331, 21990134, 25948282, 20104584, 20383589, 26295337, 18451181, 23108138, 10699917, 28324225, 29335924, 29884841, 33964450, 30787465, 29988080, 29446198, 32444794, 12228710)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218666	SCV000296502	pathogenic	not provided	2021-03-26	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals and families with breast cancer (PMID: 29335924 (2018), 25948282 (2015), 25452441 (2015), 21232165 (2011), 20104584 (2010), 18451181 (2008)), and it has been classified as pathogenic in multifactorial analysis studies (PMID: 17924331 (2007), 21990134 (2012)). Additional functional studies indicate the variant has deleterious effects on BRCA2 protein functions (PMID: 23108138 (2013), 29988080 (2018)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000218666	SCV000296832	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant results in the substitution of Isoleucine to Phenylalanine at amino acid residue 2627 of the BRCA2 protein. The Isoleucine residue is highly conserved among species and is located in a functional domain of the protein and there is a small physiochemical difference between Isoleucine and Phenylalanine (Grantham Score 21). This variant has been reported in the literature in patients and families with breast and/or ovarian cancer (PMID: 10699917, 20104584, 25452441). Also, this variant has been described as 8107A>T in the literature and is absent in population databases (rs80359014). The mutation database ClinVar contains entries for this variant (Variation ID: 52430). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein and this prediction has also been observed experimentally. Experimental studies have shown that this variant affects BRCA2 homology-directed repair activity while loss of the protein function results in cell death (PMID: 18451181, 23108138, 25146914).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077415	SCV000327756	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131675	SCV000683913	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 2627 in the DNA binding domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in homology-mediated repair and complementation of Brca2-deficient mouse embryonic stem cells (PMID: 18451181, 23108138, 29394989, 29988080, 33609447). This variant has been reported in over ten individuals affected with breast cancer (PMID: 10699917, 20104584, 20383589, 21520273, 29335924) and prostate cancer (PMID: 29368341). This variant also has been reported with a family history likelihood ratio for pathogenicity of 2.61 (PMID: 18451181), and it has been observed in six breast cancer-affected individuals of Macedonian origin, who showed significant family history of BRCA2-related cancers (PMID: 29335924). 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 Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763326	SCV000894003	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000218666	SCV001249494	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045337	SCV001338376	pathogenic	Hereditary breast ovarian cancer syndrome	2020-02-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7879A>T (p.Ile2627Phe) results in a non-conservative amino acid change in 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 251356 control chromosomes. c.7879A>T has been well reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer in literature spanning over ten years to include multifactorial probability models for assessing pathogenic outcomes (example, Borg_2010, Capanu_2011, Stegel_2011, Spitzer_2000, Kluska_2015, Couch_2015, Rebbeck_2018, Lindor_2012, Easton_2007). These data indicate that the variant is very likely to be associated with disease. At-least one co-occurrence with another pathogenic variant has been reported in a patient with triple negative breast cancer (PALB2 c.2470dupT, p.Cys824LeufsX2)(Couch_2015). However, this does not rule out the pathogenicity of this variant due to the possibility of mutual exclusivity of the two variants. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an inability to complement the lethality of mBRCA2-deficient mouse-embryonic stem (mES) cells (example, Hendriks_2014 and Mesman_2019) as well as decreased homology directed repair activity (example, Farrugia_2008, Guidguli_2012). One expert panel (ENIGMA) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=8)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000077415	SCV001428833	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-07	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PM2_SUP, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000218666	SCV001447781	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000218666	SCV002010322	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000218666	SCV002019030	pathogenic	not provided	2019-06-05	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000218666	SCV002758606	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PP3, PS3, PM1, PS4, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV001289537	SCV003804715	pathogenic	Familial cancer of breast	2023-07-18	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM2_SUP,PP3
Baylor Genetics	RCV001289537	SCV004210438	pathogenic	Familial cancer of breast	2022-12-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077415	SCV000109213	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077415	SCV000147209	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045337	SCV000587918	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000218666	SCV000592155	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Ile2627Phe variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0001) from individuals or families with bilateral and unilateral breast cancer (Borg 2010); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was identified in dbSNP (ID: rs80359014) “With Pathogenic, Uncertain significance allele.” The p.Ile2627Phe variant was also identified in GeneInsight COGR database by 2 submitters, one classified as pathogenic and the other as VUS. In Clinvar database, the variant was identified and classified as pathogenic by ENIGMA and by the Sharing Clinical Reports Project, derived from Myriad reports; it was classified as likely pathogenic by Ambry Genetics and no classification was provided by Invitae. The BRCA Share UMD Database identified the variant 1x and classified it as causal and ARUP Laboratories identified the variant 1x and classified it definitely pathogenic. In BIC database the variant was identified 7x with unknown clinical significance. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server) and Exome Aggregation Consortium (ExAC), COSMIC, Clinvitae or MutDB. The p.Ile2627 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phenylalanine (Phe) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In addition, Multifactorial likelihood-ratio modelling, homology-directed repair assay and centrosome percent amplification assay, suggest that the variant disrupts BRCA2 function (Farrugia 2008, Easton 2007). Studies on protein likelihood ratio modelling is in favour of protein loss of function (Karchin 2008) and based on multifactorial probability-based model for assessing pathogenicity, the prior probability of being deleterious is 0.29 and posterior probability of being deleterious 1.00 (Lindor 2012).In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
King Laboratory, University of Washington	RCV001171395	SCV001251298	benign	not specified	2019-09-01	no assertion criteria provided	research
Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya	RCV001289537	SCV001477299	pathogenic	Familial cancer of breast	2019-10-19	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077415	SCV002588916	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing