rs397509100
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_007294.4(BRCA1):āc.3758C>Gā(p.Ser1253Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1253F) has been classified as Likely benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.3758C>G | p.Ser1253Cys | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.3758C>G | p.Ser1253Cys | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251260Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135780
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461722Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727170
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74328
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 13, 2022 | This missense variant replaces serine with cysteine at codon 1253 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 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. - |
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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2023 | The p.S1253C variant (also known as c.3758C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3758. The serine at codon 1253 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported in an individual with ovarian cancer (Gleicher N et al. PLoS ONE. 2014 Jul;9:e102370). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces serine with cysteine at codon 1253 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 15, 2016 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 06, 2023 | In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMIDs: 32885271 (2021), 25036526 (2014)). In a large-scale breast cancer association study, this variant was observed in a breast cancer case and in a control individual (see LOVD (http://databases.lovd.nl/shared/genes/BRCA1) and PMID: 33471991 (2021)). In addition, this variant has been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000039 (5/128986 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 3877C>G; Observed in individuals with ovarian cancer (Gleicher 2014); This variant is associated with the following publications: (PMID: 25036526, 28726806, 31642931) - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1253 of the BRCA1 protein (p.Ser1253Cys). This variant is present in population databases (rs397509100, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 25036526, 34326862). ClinVar contains an entry for this variant (Variation ID: 186252). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 15, 2022 | Variant summary: BRCA1 c.3758C>G (p.Ser1253Cys) 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 1.6e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758C>G has been reported in the literature in at least one individual affected with Ovarian Cancer (example, Gleicher_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 31, 2018 | - - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
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.Ser1253Cys variant was identified in 2 of 172 proband chromosomes (frequency: 0.01) from Austrian individuals or families with ovarian cancer (Gleicher 2014); these two patients had co-occurring, unclassified BRCA2 variants. The variant was identified in dbSNP (ID: rs397509100) Ć¢ā¬Å”ĆāĆĀŗWith Uncertain significance, untested alleleĆ¢ā¬Å”ĆāĆĀ¹ and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, and GeneDx). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was also identified in control databases in 5 of 276974 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the European Non-Finnish population in 5 of 126476 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1253 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Cys variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this 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 uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at