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

dbSNP: rs80357253

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087889	SCV000075395	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-13	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Diagnostics, LLC DBA Color Health	RCV000130521	SCV000911276	benign	Hereditary cancer-predisposing syndrome	2017-01-18	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130521	SCV003846094	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000030980	SCV000053572	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-11-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030980	SCV000144033	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.
BRCAlab, Lund University	RCV000030980	SCV004244133	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758601	SCV005359972	uncertain significance	BRCA1-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The BRCA1 c.1222A>G variant is predicted to result in the amino acid substitution p.Lys408Glu. This variant has been reported in an individual undergoing testing for breast/ovarian cancer but was considered likely benign due to the Lys408 residue being a glutamic acid (Glu) in several other species (Abkevich et al. 2004. PubMed ID: 15235020). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37399/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.