ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3929C>A (p.Thr1310Lys) (rs80357257)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000589731 SCV000076396 likely benign not provided 2019-02-10 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 RCV000501619 SCV000605860 uncertain significance not specified 2017-06-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569349 SCV000665800 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Other data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000589731 SCV000699086 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3929C>A (p.Thr1310Lys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not reside within a known functional domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in ExAC at a frequency of 0.0000082 (1/121398 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant was also found in the large control database gnomAD at a frequency of 0.000077 (19/245914 control chromosomes; 1 homozygote) and was predominantly observed in the Latino subpopulation at a frequency of 0.000536 (18/33580; 1 homozygote). The variant has been reported in patients in the literature without strong evidence for pathogenicity (Spearman_BRCA2_JCO_2008; Cabanillas_MGGM_2017). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations including benign and uncertain significance. Taken together, this variant is classified as VUS until more evidence becomes available.
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 RCV000569349 SCV000911049 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-18 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

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