Submissions for variant NM_007294.4(BRCA1):c.4654T>C (p.Tyr1552His)

dbSNP: rs1265352633

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532651	SCV000635985	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1552 of the BRCA1 protein (p.Tyr1552His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and cutaneous malignant melanoma (PMID: 22713736, 29036293). This variant is also known as 4773T>C. ClinVar contains an entry for this variant (Variation ID: 433716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758836	SCV000887705	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251256 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast/ovarian cancer (PMID: 22713736 (2012)) and melanoma (PMID: 29036293 (2017)). One in vitro study showed that the wild- type tyrosine residue at this position is important for BRCA1 stability and function in DNA repair (PMID: 29156836 (2017)). However, additional functional studies are needed to assess the effect of this variant. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765359	SCV000896624	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776618	SCV000912236	likely benign	Hereditary cancer-predisposing syndrome	2017-10-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000776618	SCV001184632	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	clinical testing	The p.Y1552H variant (also known as c.4654T>C), located in coding exon 13 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4654. The tyrosine at codon 1552 is replaced by histidine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with melanoma (Goldstein AM et al. Hum Mol Genet, 2017 12;26:4886-4895) and in an individual with a family history of breast and/or ovarian cancer from Lebanon (Jalkh N et al. Hered Cancer Clin Pract, 2012 Jun;10:7). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV000776618	SCV002537765	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330731	SCV004039195	uncertain significance	not specified	2023-08-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4654T>C (p.Tyr1552His) 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. The variant allele was found at a frequency of 4e-06 in 251256 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4654T>C has been reported in the literature in individuals affected with Melanoma or Breast and/or Ovarian Cancer without strong evidence for causality (examples, Goldstein_2017, Jalkh_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29036293, 22713736). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004003514	SCV004817644	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504104	SCV000591531	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Tyr1552His variant was identified by Jalkh (2012) in a Lebanese individual with breast cancer. The variant was also identified in UMD (2X as an unclassified variant); in one of these samples it was found in co-occurrence with a pathogenic BRCA1 mutation (c.4358_4484del (p.Ala1453GlyfsX10)), increasing the likelihood that the p.Tyr1552His variant does not have clinical significance. 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. The p.Ala469Thr residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735520	SCV000863658	likely benign	Breast and/or ovarian cancer	2013-10-03	no assertion criteria provided	clinical testing