ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3776A>C (p.Asn1259Thr) (rs483353090)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159849 SCV000209893 uncertain significance not provided 2014-07-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3776A>C at the cDNA level, p.Asn1259Thr (N1259T) at the protein level, and results in the change of an Asparagine to a Threonine (AAT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Asn1259Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Asn1259Thr occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Asn1259Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001084247 SCV000259957 benign Hereditary breast and ovarian cancer syndrome 2019-10-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112181 SCV000296461 uncertain significance Breast-ovarian cancer, familial 1 2016-04-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771318 SCV000903576 likely benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779862 SCV000916731 uncertain significance not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3776A>C (p.Asn1259Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245960 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (3.3e-05 vs 1.00e-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3776A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV000771318 SCV001182683 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-30 criteria provided, single submitter clinical testing The p.N1259T variant (also known as c.3776A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 3776. The asparagine at codon 1259 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112181 SCV000144876 uncertain significance Breast-ovarian cancer, familial 1 2013-03-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357117 SCV001552472 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The BRCA1 p.Asn1259Thr variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in dbSNP (ID: rs483353090) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as uncertain significance by GeneDx and two other submiters), and in BIC (1x with unknown significance) databases. The variant was identified in control databases in 8 of 245960 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 8 of 30782 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn1259 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.

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