ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1222A>G (p.Lys408Glu) (rs80357253)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001087889 SCV000075395 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130521 SCV000185390 likely benign Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000426822 SCV000522017 likely benign not specified 2017-10-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586793 SCV000698835 uncertain significance not provided 2016-12-13 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1222A>G (p.Lys408Glu) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant is absent in 121218 control chromosomes. Clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Health, Inc RCV000130521 SCV000911276 benign Hereditary cancer-predisposing syndrome 2017-01-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000030980 SCV000053572 benign Breast-ovarian cancer, familial 1 2009-11-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030980 SCV000144033 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 RCV001358158 SCV001553823 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Lys408Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. Ther variant was reported in a study using computation analysis to classify variant as was determined to be neutral (Abkevich 2004). The variant was also identified in dbSNP (ID: rs80357253) as “With Pathogenic, other allele” as a separate variant is reported to cause a nonsense change at this loci. The variants was also identified in ClinVar (as uncertain significance by Lab Corp, BIC; likely benign by Ambry Genetics, GeneDx and Invitae and benign by Sharing Clinical Reports Project), and LOVD 3.0 (5x predicted neutral). The variant was identified in control databases in 1 of 245604 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 111140 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, EastAsian, Finnish, and South Asian populations. The p.Lys408Glu 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, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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