17-43093163-T-C
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007294.4(BRCA1):c.2368A>G(p.Thr790Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 0.181
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.06325126).
BP6
Variant 17-43093163-T-C is Benign according to our data. Variant chr17-43093163-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37465.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4, Benign=4}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.2368A>G | p.Thr790Ala | missense_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.2368A>G | p.Thr790Ala | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.000276 AC: 42AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000718 AC: 18AN: 250612Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135440
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461490Hom.: 0 Cov.: 41 AF XY: 0.0000344 AC XY: 25AN XY: 727020
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GnomAD4 genome 0.000276 AC: 42AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:10
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 28, 2020 | The BRCA1 c.2368A>G; p.Thr790Ala variant (rs41286298) is reported in the literature in multiple individuals affected with breast cancer (Cortes 2019, Haffty 2006, Lee 2008, Rummel 2013). However, this variant is also reported to co-occur with pathogenic variants in BRCA1 or BRCA2 by other laboratories in ClinVar (Variant ID: 37465), and is found in the African population with an allele frequency of 0.10% (25/24960 alleles) in the Genome Aggregation Database. The threonine at codon 790 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Although there is evidence to support a benign role for this variant, due to insufficent information, the clinical significance of is uncertain at this time. References: Cortes C et al. Mutational analysis of BRCA1 and BRCA2 genes in women with familial breast cancer from different regions of Colombia. Hered Cancer Clin Pract. 2019 Jul 15;17:20. Haffty BG et al. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet. 2006 Feb;43(2):133-7. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19. Rummel S et al. Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat. 2013 Jan;137(1):119-25. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 01, 2021 | The p.Thr790Ala variant in BRCA1 has been reported in at >10 individuals with breast or ovarian cancer, the majority of which were Black or African-American (Haffty 2005 PMID: 15983021, Lee 2008 PMID: 18284688, Rummel 2013 PMID: 23192404, Pal 2015 PMID: 26287763, Cortes 2019 PMID: 31341521, Cotrim 2019 PMID: 30606148; Breast Cancer information Core (BIC)). It has also been identified in 0.1% (25/24960) of African or African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 37465). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, including the presence of Alanine (Ala) at this position in two mammals, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these frequency and lack of conservation suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PS4_Moderate, BP4, BS1_Supporting. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 07, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2020 | This variant is associated with the following publications: (PMID: 15983021, 23192404, 16267036, 22875147, 18284688, 16518693, 31341521, 30606148) - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 17, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 30, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2019 | 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. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 12, 2020 | - - |
| Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 25, 2008 | - - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 13, 2018 | Variant summary: BRCA1 c.2368A>G (p.Thr790Ala) 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 9.9e-05 in 282008 control chromosomes, predominantly within the African subpopulation at a frequency of 0.001 in the gnomAD database. This frequency is about the same as expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001 vs 0.001), suggesting a benign role for the variant. c.2368A>G has been reported in the literature in several individuals of African and/or African American ancestry affected with Hereditary Breast and Ovarian Cancer. Due to the similarity in the ethnicity between control chromosomes and published reports, these occurrences do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic BRCA1 variants have been reported in the UMD database (c.5324T>G (p.Met1775Arg) in one individual and c.1961dup (p.Tyr655valfsX18) in another), in addition, several co-occurrences with pathogenic BRCA2 variants have also been reported (in the BIC database: c.5946_5946delT (p.Ser1982fsX22) in one individual, and c.8948_8953+5delATTCAGGTAAG in two other individuals; and in LCA internal samples: c.2808delA (p.Lys936fsX24) in one individual and c.5351dupA (p.Asn1784fsX3) in another individual). These multiple co-occurrences strongly support a benign role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (1x) / Likely benign (2x). Based on the evidence outlined above, the variant was re-classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 03, 2022 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Nov 04, 2013 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Thr790Ala variant was identified in the literature in an African American individual with breast cancer; however, control chromosomes from healthy individuals were not evaluated in this study (Haffty 2005). The variant was also identified in dbSNP (ID: rs41286298) “With unknown allele”, BIC (8X with unknown clinical importance) and UMD (1X as an unclassified variant). Within the UMD record, the variant was noted to co-occur with a known pathogenic mutation in BRCA1 (c.5324T>G (p.Met1775Arg)), increasing the likelihood that the p.Thr790Ala variant may not have clinical significance. In addition, the variant was reported in three of 4460 African American chromosomes (frequency: 0.0007) from the Exome Variant Server ESP Project, increasing the likelihood that may be a low frequency benign variant in certain populations of origin. The p.Thr790 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of 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. - |
BRCA1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.
REVEL
Uncertain
Sift
Benign
T;T;T;D;.
Sift4G
Benign
T;T;T;D;.
Polyphen
P;.;.;P;.
Vest4
MVP
MPC
0.15
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at