Submissions for variant NM_007294.4(BRCA1):c.2662C>T (p.His888Tyr)

gnomAD frequency: 0.00002  dbSNP: rs80357480

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081135	SCV000075927	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129905	SCV000184723	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-11	criteria provided, single submitter	clinical testing	The p.H888Y variant (also known as c.2662C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2662. The histidine at codon 888 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in multiple ethnically diverse patients/families with suspected hereditary breast and/or ovarian cancer (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259; Miramar MD et al. Breast Cancer Res. Treat. 2008 Nov; 112(2):353-8; Alvarez C et al. Oncotarget. 2017 Sep;8:74233-74243; Gabaldó Barrios X et al. Fam Cancer. 2017 10;16:477-489; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). In one study, this variant was reported in 4/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000589310	SCV000210134	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Observed in individuals with familial breast cancer or other history warranting hereditary cancer testing (PMID: 12938098, 16267036, 18176857, 29088781, 28477318, 27616075, 31159747, 33471991); Published functional studies demonstrate no damaging effect: homologous recombination repair activity comparable to wild-type (PMID: 32546644); 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 2781C>T; This variant is associated with the following publications: (PMID: 16267036, 12938098, 28477318, 18176857, 15385441, 27616075, 29088781, 26206375, 25348012, 22144684, 24393486, 31159747, 31294896, 31131967, 31112341, 34597585, 32377563, 33875564, 29884841, 10923033, 31911673, 33630411, 33471991, 34981296, 32546644, 15343273, 38725546)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768614	SCV000324815	uncertain significance	Breast and/or ovarian cancer	2016-02-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000111910	SCV000488138	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047914	SCV000698971	benign	not specified	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2662C>T (p.His888Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as Class 2 (Likely not pathogenic) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). The variant allele was found at a frequency of 2e-05 in 251050 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2662C>T has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer or colorectal cancer (example, Judkins 2005, Meyer 2003, Miramar 2008, Kraus 2016, Alvarez 2017, Gabaldo 2017, Tsaousis_2019, Ferrer-Avargues_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (UMD database - BRCA2 c.5073dup, p.Trp1692MetfsX3; Ferrer-Avargues_2021 - MSH6 c.3996_4000dup, p.Arg1334HisfsTer), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function in a homologous recombination DNA repair (HRR) complementation assay (example, Bouwman_2020). These results showed no damaging effect of this variant. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/Likely Benign, n=2; VUS, n=8). Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA	RCV000129905	SCV000821918	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129905	SCV000910804	benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589310	SCV001133532	uncertain significance	not provided	2024-08-05	criteria provided, single submitter	clinical testing	The BRCA2 c.2662C>T (p.His888Tyr) variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 34981296 (2022), 31159747 (2019), 29088781 (2017), 28477318 (2017), 27616075 (2016), 18176857 (2008), 12938098 (2003)). This variant has also been identified in individuals with breast cancer as well as reportedly healthy individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). A published functional study has reported that this variant does not have a deleterious effect on BRCA1 protein function (PMID: 32546644 (2020)). The frequency of this variant in the general population, 0.000035 (4/113480 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000111910	SCV001140571	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000589310	SCV001716307	uncertain significance	not provided	2020-11-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129905	SCV002538144	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129905	SCV003851004	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Revvity Omics, Revvity	RCV000589310	SCV004234651	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016336	SCV005647158	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-05-04	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111910	SCV000144502	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589310	SCV000591401	uncertain significance	not provided		no assertion criteria provided	clinical testing