rs80357127
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.2726A>T(p.Asn909Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,856 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N909Y) has been classified as Likely benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.2726A>T | p.Asn909Ile | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2726A>T | p.Asn909Ile | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000798 AC: 20AN: 250780Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135502
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461660Hom.: 0 Cov.: 47 AF XY: 0.0000220 AC XY: 16AN XY: 727120
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 14, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 22, 1999 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2015 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 08, 2022 | - - |
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). - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2020 | 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 | Jul 15, 2020 | - - |
not specified Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2023 | Variant summary: BRCA1 c.2726A>T (p.Asn909Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 279764 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2726A>T has been reported in the literature in individuals of Asian ancestry who were affected by breast or ovarian cancer, but was also found in healthy controls (e.g. Lai, 2017; Ahmadloo, 2017, Bhaskaran_2019, Kwong_2020, Momozawa_2018, Dorling_2021, Zhang_2022). In addition, a study classified this variant as likely benign based on a multifactorial probability model (Lee_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18627636, 22217648, 27257965, 26852015, 28364669, 28179634, 12602912, 29176636, 30287823, 30702160, 28222693, 30415210, 32068069, 35918668). Ten other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 17, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 05, 2016 | - - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2018 | This variant is denoted BRCA1 c.2726A>T at the cDNA level, p.Asn909Ile (N909I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAT>ATT). Using alternate nomenclature, this variant has been previously published as BRCA1 2845A>T. This variant has been observed in individuals with a personal and/or family history of breast cancer, all of whom were of Asian ancestry, and was detected in 5/2091 breast cancer cases and 4/1462 controls in a study of multi-ethnic Asian individuals (Chen 2003, Thirthagiri 2008, Jang 2012, Cao 2016, Zhong 2016, Ahmadloo 2017, Arai 2017, Lai 2017, Park 2017). BRCA1 Asn909Ile was observed at an allele frequency of 0.12% (20/17,248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in DNA binding domain and in a region reported to interact with RAD51 (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Asn909Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
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.Asn909Ile variant was identified in 21 of 23988 proband chromosomes (frequency: 0.0009) from individuals or families with breast or ovarian cancer and was present in 18 of 25598 control chromosomes (frequency: 0.0007) from healthy individuals (Arai 2018, Bhaskaran 2019, Cao 2016, Chen 2003, Jang 2012, Lai 2017, Momozawa 2018, Thirthagiri 2008). The variant was also identified in dbSNP (ID: rs80357127) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics, GeneDx and seven other submitters), LOVD 3.0 (6x), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 20 of 245542 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 20 of 17248 chromosomes (freq: 0.001), increasing the likelihood this could be a low frequency benign variant, while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Asn909 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at