Submissions for variant NM_007294.4(BRCA1):c.3416G>T (p.Ser1139Ile)

gnomAD frequency: 0.00001  dbSNP: rs80357228

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112090	SCV001161584	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000012
Invitae	RCV000048184	SCV000076197	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132045	SCV000187105	likely benign	Hereditary cancer-predisposing syndrome	2021-06-07	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112090	SCV000195919	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000235128	SCV000210146	likely benign	not provided	2020-03-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency 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: 20104584, 12938098, 23704879, 31131967, 16267036, 10923033)
Color Diagnostics, LLC DBA Color Health	RCV000132045	SCV000902967	likely benign	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194406	SCV001363931	likely benign	not specified	2023-11-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3416G>T (p.Ser1139Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 1455818 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (1.2e-05 vs 0.001), allowing no conclusion about variant significance. c.3416G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Borg_2010, Meyer_2003, Bhai_2021), however without strong evidence for causality (e.g., lack of co-segregation data). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Bouwman_2020). The results of this study showed no damaging effect of this variant on homology directed repair (HDR) activity by illustrating no impairment of the variant to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using a direct GFP HRR assay as well as cisplatin and olaparib sensitivity assays. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group (PMID: 31892348). ClinGen SVI now recognizes benign functional evidence as sufficient for categorization as likely benign (PMID: 29300386). The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 12938098, 34326862, 32546644, 16267036, 34396183). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (benign/likely benign, n = 6; uncertain significance, n = 3). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001194406	SCV002070149	uncertain significance	not specified	2020-02-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.3416G>T, in exon 10 that results in an amino acid change, p.Ser1139Ile. This sequence change does not appear to have been previously described in patients with BRCA1-related disorders and has been described in the gnomAD database in three individuals (dbSNP rs80357228). The p.Ser1139Ile change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Ser1139Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Ser1139Ile change remains unknown at this time.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001194406	SCV002551000	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554660	SCV004120319	uncertain significance	BRCA1-related disorder	2023-08-05	criteria provided, single submitter	clinical testing	The BRCA1 c.3416G>T variant is predicted to result in the amino acid substitution p.Ser1139Ile. This variant was reported in at least one patient with breast cancer, however, no other information was available (for example, supple. Table 2 in Borg et al. 2010. PubMed ID: 20104584). Of note, this variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41244132-C-A). This variant is classified as benign, or uncertain variant in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/54873/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235128	SCV004219354	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113598 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 12938098 (2003), 16267036 (2005), 20104584 (2010), and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). This variant was also reported in healthy cancer-free individuals (FLOSSIES, (https://whi.color.com/), PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112090	SCV000144756	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000048184	SCV000586892	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-14	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112090	SCV004244045	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing