ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3929C>A (p.Thr1310Lys) (rs80357257)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048383 SCV000076396 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000589731 SCV000209964 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3929C>A at the cDNA level and p.Thr1310Lys (T1310K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant, also defined as BRCA1 c.4048C>A using alternate nomenclature, has been observed in at least one breast cancer patient and is predicted to be neutral by a tumor analysis model based on factors such as receptor status, tumor grade, and loss of heterozygosity (Spearman 2008). This variant was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. This variant occurs at a position that is not conserved and is located within the SCD domain and in a region known to interact with multiple proteins (Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Thr1310Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589731 SCV000605860 likely benign not provided 2019-12-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569349 SCV000665800 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-24 criteria provided, single submitter clinical testing The p.T1310K variant (also known as c.3929C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3929. The threonine at codon 1310 is replaced by lysine, an amino acid with similar properties. This alteration was identified in a cohort of long-term pancreatic cancer survivors from the Czech Republic (Lovecek M et al. Cancer Manag Res. 2019 Jan;11:599-609). This alteration has been classified as a variant of unknown significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, tumor characteristics, and mutation co-occurrence (Spearman AD et al. J. Clin. Oncol. 2008 Nov;26:5393-400). This amino acid position is not well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501619 SCV000699086 uncertain significance not specified 2020-08-14 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation sites (PMID: 22193408). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 394484 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation (i.e. 51/48248 alleles) in the gnomAD database (v2.1 exomes dataset and v3 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. To our knowledge, the variant, c.3929C>A, has been reported in the literature in at least two individuals, who were affected with breast- and pancreatic carcinoma (Spearman_2008, Lovecek_2019). These reports however, 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and six of them classified the variant as VUS, while one called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl RCV000083201 SCV000786541 uncertain significance Breast-ovarian cancer, familial 1 2018-05-22 criteria provided, single submitter clinical testing
Mendelics RCV000048383 SCV000839243 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000569349 SCV000911049 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083201 SCV000115275 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083201 SCV000144917 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000589731 SCV001553543 uncertain significance not provided no assertion criteria provided clinical testing

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