rs80357104
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5165C>T(p.Ser1722Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1722A) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5165C>T | p.Ser1722Phe | missense_variant | 18/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5165C>T | p.Ser1722Phe | missense_variant | 18/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459212Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726170
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7Uncertain:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 25, 2017 | The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This missense variant replaces serine with phenylalanine at codon 1722 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have consistently shown that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603). This variant has been reported in at least six individuals affected with hereditary breast and/or ovarian cancer (PMID: 22476429, 33526602; Color internal data). An external laboratory has concluded this variant to be Pathogenic based on analysis of personal and family history of 44 probands (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 19, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 17, 2012 | - - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 11, 2021 | Variant summary: BRCA1 c.5165C>T (p.Ser1722Phe) results in a non-conservative amino acid change located in the first BRCT domain (IPR001357) that binds ATM-phosphorylated proteins (e.g. abraxas, CtIP and BRIP1; see PMID 22193408). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251036 control chromosomes (gnomAD). c.5165C>T has been reported in the literature in individuals with personal and/or family history of breast- and ovarian cancer (Judkins_2005, Lu_2012, Chan_2018, Lynce_2020). Publications also reported experimental evidence, demonstrating decreased structural stability, impaired phosphopeptide binding and transcriptional activity (Lee_2010); and in a recent high throughput genome editing assay the variant resulted in a decreased (intermediate) function when testing it in a haploid human cell line whose survival is dependent on intact BRCA1 function (Findlay_2018). Ten other 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 pathogenic (n=2) or likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 12, 2021 | The c.5165C>T (p.Ser1722Phe) variant in the BRCA1 gene has been reported in two patients in the Breast Cancer Information Core database (accession number 10462 and 10461). The variant has also been reported in additional patients by clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55441). Functional assays showed a strong deleterious effect [PMID 20516115]. This variant was not observed in the ExAC database. Serine at amino acid position 1722 of the BRCA1 protein is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Ser1722Phe change to be deleterious. This variant thus classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 23, 2020 | The p.Ser1722Phe variant in BRCA1 has been reported in at least 3 individual with breast cancer (Lu 2012, Breast Information Core (BIC) database). In addition, this variant has also been reported in ClinVar (Variation ID 55441) and was absent from large population databases. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Lee 2010, Carvalho 2002 ). In addition, this variant lies within a binding motif in BRCA1. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Hereditary breast and ovarian cancer. PM1, PM2, PP3, PS3_Supporting, PS4_Supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1722 of the BRCA1 protein (p.Ser1722Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22476429, 28888541, 30093976, 35264596). ClinVar contains an entry for this variant (Variation ID: 55441). 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 expected to disrupt BRCA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12496477, 20516115). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 29, 2021 | This variant has been reported in individuals and families affected with breast/ovarian cancer (PMID: 16267036 (2005), 22476429 (2012), 29446198 (2018), 30093976 (2018), 30264118 (2018), 31481248 (2019), 33010199 (2020)) and described as pathogenic based on a multifactorial likelihood algorithm in the published literature (PMID: 25085752 (2014)). In addition, functional studies describe the p.Ser1722Phe variant as having a deleterious effect on BRCA1 protein function (PMID: 12496477 (2002), 15172985 (2004), 20516115 (2010)). Based on the available information, this variant is classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2023 | Published functional studies demonstrate a damaging effect with respect to protein folding, phosphopeptide binding activity and specificity, transcriptional activity, homology-directed repair, and cell viability (Carvhalo et al., 2002; Lee et al., 2010; Findlay et al., 2018; Fernandes et al., 2019; Iversen et al., 2022); Observed in individuals with BRCA1-related cancers (Lu et al., 2012; Chan et al., 2018; Mersch et al., 2018; Ow et al., 2019; Guindalini et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5284C>T; This variant is associated with the following publications: (PMID: 15172985, 30209399, 16267036, 20516115, 25085752, 12496477, 17305420, 22476429, 28781887, 15385441, 29446198, 23704879, 30264118, 30093976, 30765603, 31447099, 33087888, 30875412, 30787465, 33526602, 25348405, 32377563, 35665744, 29884841, 35264596, 33206196, 33010199) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 08, 2022 | This missense variant replaces serine with phenylalanine at codon 1722 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have consistently shown that this variant results in the loss of transcription activation function of BRCA1 protein (PMID: 12496477, 15172985, 20516115, 30765603). This variant has been reported in at least six individuals affected with hereditary breast and/or ovarian cancer (PMID: 22476429, 33526602; Color internal data). An external laboratory has concluded this variant to be Pathogenic based on analysis of personal and family history of 44 probands (PMID: 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2021 | The p.S1722F pathogenic mutation (also known as c.5165C>T), located in coding exon 17 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5165. The serine at codon 1722 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Based on multiple structural and functional analyses, this alteration was shown to significantly alter protease sensitivity, peptide binding activity, peptide binding specificity, and transcriptional activity of the mutant protein compared to wild type (Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 14, 2021 | - - |
Malignant tumor of breast Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Ser1722Ph variant falls within the BRCA1 C-terminus (BRCT) domain and was shown, in a yeast based transcription activation assay, to be temperature sensitive whereby activity was abolished at 37oC, and therefore likely represents a cancer-associated variant (Carvalho 2002). Lee et al (2010) used 3 biochemical and cell-based transcriptional assays to show that the variant had a strong functional effect and is likely associated with increased cancer risk. Other functional/computational models validated by such biochemical assays have also shown the variant to be deleterious (Mirkovic 2004, Karchin 2007). The variant was also identified in dbSNP (ID: rs80357104) “With other allele”, but no frequency information was provided, the variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) or the 1000 Genomes Browser. The variant was present in the Clinvitae database, the ClinVar database (with conflicting interpretations of pathogenicity: classified as pathogenic by Sharing Clinical Reports Project derived from Myriad reports; uncertain significance by BIC, and classification not provided by Invitae), Fanconi Anemia Mutation Database (LOVD), COSMIC (1x in a cervical tissue/squamous cell carcinoma), the BIC database (2X with unknown clinical importance), and UMD (1X with a 3-UV ”unclassified variant”). The p.Ser1722 residue is conserved across mammals and most other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at