Submissions for variant NM_007294.4(BRCA1):c.1228G>A (p.Ala410Thr)

gnomAD frequency: 0.00001  dbSNP: rs779974365

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766408	SCV000294008	uncertain significance	not provided	2016-02-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1228G>A at the cDNA level, p.Ala410Thr (A410T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 c.1347G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala410Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ala410Thr occurs at a position that is not conserved and is located in a binding domain known to interact with multiple proteins (Zhang 1998, Chai 1999, Narod 2004, Harte 2010, Zhong 1999). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ala410Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236916	SCV000600242	uncertain significance	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567869	SCV000668456	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-25	criteria provided, single submitter	clinical testing	The p.A410T variant (also known as c.1228G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1228. The alanine at codon 410 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000810492	SCV000950695	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 410 of the BRCA1 protein (p.Ala410Thr). This variant is present in population databases (rs779974365, gnomAD 0.007%). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 246448). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236916	SCV001362760	uncertain significance	not specified	2024-02-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1228G>A (p.Ala410Thr) 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 allele was found at a frequency of 4e-06 in 250802 control chromosomes (gnomAD). 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.1228G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. The following publication has been ascertained in the context of this evaluation (PMID: 32546644). ClinVar contains an entry for this variant (Variation ID: 246448). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000567869	SCV003846090	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).
Myriad Genetics, Inc.	RCV004591095	SCV005084445	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-20	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].