Submissions for variant NM_007294.4(BRCA1):c.1405G>A (p.Ala469Thr)

dbSNP: rs397507187

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165869	SCV000216618	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	The p.A469T variant (also known as c.1405G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1405. The alanine at codon 469 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000587317	SCV000293744	uncertain significance	not provided	2020-06-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28726806)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526449	SCV000635795	benign	Hereditary breast ovarian cancer syndrome	2024-11-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236685	SCV000698861	uncertain significance	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1405G>A (p.Ala469Thr) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251154 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1405G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.3599_3600delGT, p.Asp1199_Cys1200insTer), providing supporting evidence for a benign role. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587317	SCV000887623	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	The BRCA1 c.1405G>A (p.Ala469Thr) variant has been reported in the published literature in at least one individual with breast cancer (PMID: 34326862 (2021)) as well as a reportedly healthy individual (PMID: 30287823 (2018))), and is described to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000165869	SCV000911274	likely benign	Hereditary cancer-predisposing syndrome	2017-01-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165869	SCV002538023	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149591	SCV003838906	uncertain significance	Breast and/or ovarian cancer	2021-10-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165869	SCV003851319	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).
Fulgent Genetics, Fulgent Genetics	RCV005016303	SCV005647176	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-03-13	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030992	SCV000053584	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-05-06	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000030992	SCV000591329	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Ala469Thr variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, or BIC databases. The variant was classified as a variant with uncertain significance by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). 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. The p.Ala469Thr 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. 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 unknown significance.