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rs41293463

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_007294.4(BRCA1):c.5324T>G(p.Met1775Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,936 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1775K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

10
6
1

Clinical Significance

Pathogenic reviewed by expert panel P:19U:1O:1

Conservation

PhyloP100: 5.03
Variant links:
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 Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 17 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43051071-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 17695.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901
PP5
Variant 17-43051071-A-C is Pathogenic according to our data. Variant chr17-43051071-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17694.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051071-A-C is described in Lovd as [Pathogenic]. Variant chr17-43051071-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.5324T>G p.Met1775Arg missense_variant 20/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.5324T>G p.Met1775Arg missense_variant 20/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251394
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461792
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:19Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7Uncertain:1Other:1
Pathogenic, criteria provided, single submitterclinical testingGenologica MedicaJan 01, 2017- -
Pathogenic, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Aug 10, 2015IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Pathogenic, criteria provided, single submitterclinical testingCounsylJul 14, 2015- -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 07, 2006- -
not provided, no classification providedin vitroBrotman Baty Institute, University of Washington-- -
Pathogenic, criteria provided, single submitterclinical testingConsortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of CambridgeOct 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 16, 2023- -
Pathogenic, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)May 01, 2012- -
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 27, 2023This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1775 of the BRCA1 protein (p.Met1775Arg). This variant is present in population databases (rs41293463, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 7545954, 7939630, 22144684). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17694). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12400015, 14534301, 19493677, 20516115, 23161852). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 20, 2016Variant summary: The BRCA1 c.5324T>G (p.Met1775Arg) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Methionine (M) with a large size and basic Arginine (R) located in the BRCT domain. Consistently, 5/5 in silico tools predict a damaging outcome for this variant. The variant is absent in 124492 control chromosomes while it was reported in several HBOC patients including one family in which it was shown to co-segregate with the disease, indicating its pathogenicity. Moreover, functional studies demonstrated the variant to impair homology directed repair, single strand annealing, phosphopeptide-binding and transcriptional activity of BRCA1 further supporting a deleterious impact. Additionally, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoDec 17, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 09, 2023The p.Met1775Arg variant in BRCA1 has been reported in >20 individuals with BRCA1-associated cancers, with a higher prevalence in those of African descent and segregated with disease in many affected relatives from a large family (Futreal 1994 PMID: 7939630, Miki 1994 PMID: 7545954, Hall 2009 PMID: 19241424, Fackenthal 2012 PMID: 22034289, Pal 2015 PMID: 26287763, BIC database). It has also been identified in 0.002% (1/41432) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. In vitro functional studies support an impact on protein function (Kawai 2002 PMID: 12400015, Caligo 2009 PMID: 18680205, Lee 2010 PMID: 20516115, Findlay 2018 PMID: 30209399) and computational prediction tools and conservation analysis suggest that the p.Met1775Arg variant may impact the protein. Additionally, this variant has been classified in ClinVar as Pathogenic on Aug 10, 2015 by the ClinGen-approved ENIGMA expert panel (Variation ID: 17694). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM2_Supporting, PS3_Moderate, PP3. -
Pathogenic, no assertion criteria providedresearchHereditary Cancer Genetics group, Vall d'Hebron Institute of OncologyMar 01, 2019- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 20, 2022Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (Lindor 2012); Published functional studies demonstrate a damaging effect: abolishes BRCA1 activity, including double strand break repair, transcription, and binding functions (Monteiro 1996, Kawai 2002, Williams 2003, Varma 2005, Towler 2013); Observed in many individuals with hereditary breast and ovarian cancer and has been reported as a recurrent variant in the African population (Futreal 1994, Miki 1994, Zhang 2012, Donenberg 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5443T>G; This variant is associated with the following publications: (PMID: 21666281, 19493677, 25782689, 17305420, 17308087, 16101277, 15133503, 15967981, 22739995, 26287763, 27495310, 23994874, 22646717, 21447777, 21520273, 8872468, 21922593, 18680205, 15235020, 7939630, 23161852, 12400015, 12427738, 16452482, 8942979, 20516115, 20737206, 11301010, 15133502, 17005433, 17063491, 1749388, 15689452, 16786532, 14729053, 20378548, 27469594, 7545954, 16528612, 27272900, 26681312, 28398198, 25085752, 29337092, 29106372, 28781887, 30209399, 29446198, 31343793, 33087888, 33087929, 30322717, 30765603, 31998812, 30787465, 33646313, 21990134) -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 27, 2019This variant has been reported in individuals and families affected with breast or ovarian cancer in the published literature (PMID: 7939630 (1994) and 7545954 (1994)). It has also been reported to be damaging to BRCA1 protein function (PMID: 23161852 (2013), 20516115 (2010), 19493677 (2009), 14534301 (2003), 12400015 (2002)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Met1775Arg variant was identified in the UMD 2X as a causal variant, in BIC 31X as a variant of unknown clinical importance, and also in the HGMD and LOVD databases. The variant was identified in dbSNP (ID#rs41293463) as a clinically associated SNP, with no population frequency data. In addition, this variant was not identified in 1000 control chromosomes from healthy individuals from one study (Phelan 2005), and was not reported in the Exome Variant Server ESP Project. This variant has been found to segregate with disease in one kindred (Miki 1994). The p.Met1775 residue is conserved across mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Met1775Arg variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Several functional studies have concluded that this variant has a deleterious effect on BRCA1 protein function. The mutation has been shown to inhibit the interaction of BRCA1 with the DNA helicase BACH1 (Clapperton 2004, Shiozaki 2004) and with the transcriptional corepressor CtIP (Varma 2005), and yeast and mammalian cell-based assays have demonstrated that the variant impairs transcription activation (Monteiro 1996, Phelan 2005, Tischkowitz 2008). One study utilized a proteolytic sensitivity assay which indicated that the variant results in a folding defect in the BRCT domains, and thus destabilization of this domain (Williams 2003). The authors of this study suggest that this abrogates BRCA1 function, and may explain the spectrum of defects observed in other studies. In summary, based on the above information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 20, 2021The BRCA1 c.5324T>G; p.Met1775Arg variant (rs41293463), also known as 5443T>G for traditional nomenclature, is reported in the literature in several individuals and families with hereditary breast and ovarian cancer syndrome (Carter 2018, Futreal 1994, Miki 1994), and shown to co-segregate with disease in at least one family (Miki 1994). Functional analyses of the variant protein show reduced protein stability and a severe impact on BRCA1 function (Caligo 2009, Fernandes 2019, Lee 2010, Towler 2013, Williams 2003). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 17694). This variant is found in the general population with an overall allele frequency of 0.001% (4/282786 alleles) in the Genome Aggregation Database. The methionine at codon 1775 is located in the highly conserved BRCT repeat domain of BRCA1, and computational analyses predict that this variant is deleterious (REVEL: 0.728). Based on available information, this variant is considered to be pathogenic. References: Caligo MA et al. A yeast recombination assay to characterize human BRCA1 missense variants of unknown pathological significance. Hum Mutat. 2009 Jan;30(1):123-33. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. Fernandes VC et al. Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. J Biol Chem. 2019 Apr 12;294(15):5980-5992. Futreal PA et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120-2. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. Miki Y et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66-71. Towler WI et al. Analysis of BRCA1 variants in double-strand break repair by homologous recombination and single-strand annealing. Hum Mutat. 2013 Mar;34(3):439-45. Williams RS et al. Detection of protein folding defects caused by BRCA1-BRCT truncation and missense mutations. J Biol Chem. 2003 Dec 26;278(52):53007-16. -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 04, 2024This missense variant replaces methionine with arginine at codon 1775 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and protease sensitivity and protein-protein binding assays (PMID: 8942979, 9738006, 11301010, 12427738, 15689452, 23161852, 30209399). This variant has been reported as a recurring mutation and detected in multiple individuals affected with breast and/or ovarian cancer (PMID: 7837387, 7939630, 18284688, 19491284, 20104584, 24240112, 26287763, 27469594, 29337092, 34204722). This variant also has been reported to segregate with disease in a large pedigree with 24 cases of breast and ovarian cancer (PMID: 7545954). This variant has been identified in 4/282786 chromosomes 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 submitterclinical testingAmbry GeneticsMar 25, 2021The p.M1775R pathogenic mutation (also known as c.5324T>G), located in coding exon 19 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by arginine, an amino acid with similar properties. One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). Numerous other functional studies have also found this variant to be deleterious (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee M et al. Hum. Mutat. 2012 Jan;33:22-8; Towler WI et al. Hum Mutat. 2013 Mar;34:439-45; Petitalot A et al. Mol Cancer Res. 2019 01;17:54-69). The p.M1775R alteration was also identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). This alteration is located in the highly conserved BRCT repeat domain of BRCA1 and has been shown to have a severe impact on normal BRCA1 function/activity (Carvalho M et al. Cancer Res. 2007 Feb;67:1494-501; Nikolopoulos G et al. Biochim. Biophys. Acta. 2007 Jun;1774:772-80). Of note, this alteration is also designated as 5443T>G in some published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 06, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.39
Cadd
Uncertain
24
Dann
Uncertain
0.99
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.69
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-4.3
D;N;.;D;.;.;N;D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0030
D;D;.;D;.;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;.;.;D;.;.
Vest4
0.98
MVP
0.96
MPC
0.55
ClinPred
0.94
D
GERP RS
5.2
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.95
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41293463; hg19: chr17-41203088; API