Submissions for variant NM_007294.4(BRCA1):c.5481G>A (p.Met1827Ile)

gnomAD frequency: 0.00001  dbSNP: rs587782432

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131490	SCV000186478	likely benign	Hereditary cancer-predisposing syndrome	2020-11-17	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533729	SCV000636046	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-31	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1827 of the BRCA1 protein (p.Met1827Ile). This variant is present in population databases (rs587782432, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 142395). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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.
Color Diagnostics, LLC DBA Color Health	RCV000131490	SCV000688636	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1827 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported that this variant does not impact BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005886). This variant has been identified in 2/250954 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985444	SCV001133638	uncertain significance	not provided	2018-11-19	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251996	SCV002523773	uncertain significance	See cases	2020-08-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, BP4
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001076304	SCV004171419	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-14	criteria provided, single submitter	clinical testing	The BRCA1 c.5481G>A (p.Met1827Ile) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however a saturation genome editing assay has shown that this change does not affect BRCA1 function (PMID: 30209399). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in the literature in individuals with hereditary breast and ovarian cancer or Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001076304	SCV004817539	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1827 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported that this variant does not impact BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005886). This variant has been identified in 2/250954 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001076304	SCV005402624	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh38:17:43045789:C>T was assigned evidence codes ['BS3', 'BP4'] and an overall classification of Likely benign
GeneDx	RCV000985444	SCV005439270	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate no damaging effect: variant classified as functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 30209399); Also known as 5600G>A; This variant is associated with the following publications: (PMID: 30209399, 25348405)
Fulgent Genetics, Fulgent Genetics	RCV005016450	SCV005647113	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-02-06	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV001076304	SCV001242025	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro