17-43106478-A-C

Position:

chr17-43106478-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001407853.1(BRCA1):c.2T>G(p.Met1?) variant causes a start lost, splice region change. The variant allele was found at a frequency of 0.00000187 in 1,602,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA1
NM_001407853.1 start_lost, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13U:2O:1

Conservation

PhyloP100: 4.88

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]

BRCA1 links:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-43106478-A-C is Pathogenic according to our data. Variant chr17-43106478-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106478-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.190T>G	p.Cys64Gly	missense_variant	4/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.190T>G	p.Cys64Gly	missense_variant	4/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000120

AC:

AN:

250804

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135586

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:

6.90e-7

AC:

AN:

1450124

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

722022

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

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:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:6Uncertain:1Other:1

Pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 04, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 02, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces cysteine with glycine at codon 64 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). RNA study has observed that this variant causes an increase in cryptic out-of-frame splicing in exon 4 (PMID: 12915465) and functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399). This variant has been detected in at least 7 individuals and families affected with breast and ovarian cancers, and this variant was found to segregate with disease in a large pedigree with a LOD score of 2.74 (PMID: 7894491, 9042907, 9816013, 25428789, 26250392, 26689913, 28831036). This variant has been identified in 3/250804 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 submitter	clinical testing	Baylor Genetics	Apr 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 64 of the BRCA1 protein (p.Cys64Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357064, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 7894491, 9042907, 26689913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17660). 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: 20103620, 23161852). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12915465, 26689913; Invitae). This variant disrupts the p.Cys64 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11320250, 18489799, 22034289, 24516540). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2019	The p.Cys64Gly variant in BRCA1 has been identified in at least 13 individuals with BRCA1-associated cancers and segregated with disease in at least 6 individuals from 2 families (Thompson 2002, Lynce 2015, Lu 2015, Serova 1997, Rebbeck 2018, Castilla 1994, Maxwell 2017). In addition, this variant has also been reported in ClinVar (Variation ID 17660). This variant has also been identified in 3/16182 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 and in vivo functional studies support an impact on protein function (Findlay 2018, Wu 1996, Ruffner 2001, Yang 2003, Bouwman 2013, Towler 2013, Morris 2006, Lu 2015, Castilla 1994, Ransburgh 2010, Starita 2015, Maxwell 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1_Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2023	Variant summary: BRCA1 c.190T>G (p.Cys64Gly) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Yang_2003). The variant allele was found at a frequency of 1.2e-05 in 251096 control chromosomes. This variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Castilla_1994, Lynce_2015, Tung_2015, Shih_2000, Serova_1997, Palmer_2020). These data indicate that the variant is very likely to be associated with disease. Functional studies using HeLa cells confirmed this variant to be deleterious by using homology-directed recombination (HDR) and single-strand annealing (SSA) assays (Ransburgh_2010, Towler_2013). Seven 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2023	Published functional studies demonstrate a damaging effect: defective homologous recombination and single-strand annealing repair, impaired BARD1 binding, and abrogation of ubiquitin ligase activity (Wu et al., 1996; Brzovic et al., 2003; Ransburgh et al., 2010; Bouwman et al., 2013; Towler et al., 2013; Lu et al., 2015); Observed in individuals with familial breast and/or ovarian cancer (Castilla et al., 1994; Churpek et al., 2015; Lynce et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 309T>G; This variant is associated with the following publications: (PMID: 23867111, 7894491, 23161852, 20103620, 25428789, 26689913, 26295337, 29922827, 26250392, 8944023, 12732733, 12915465, 12438698, 9167459, 27977889, 25823446, 28831036, 30209399, 30696104, 25186627, 24516540, 22034289, 18489799, 16140926, 11927492, 11320250, 11106241, 29446198, 25525159, 33087888, 30787465, 32832836, 30736435, 24389207, 20104584) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 08, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2023	This missense variant replaces cysteine with glycine at codon 64 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). RNA study has observed that this variant causes an increase in cryptic out-of-frame splicing in exon 4 (PMID: 12915465) and functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399). This variant has been detected in at least 7 individuals and families affected with breast and ovarian cancers, and this variant was found to segregate with disease in a large pedigree with a LOD score of 2.74 (PMID: 7894491, 9042907, 9816013, 25428789, 26250392, 26689913, 28831036). This variant has been identified in 3/250804 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 submitter	clinical testing	Ambry Genetics	Nov 22, 2021	The p.C64G pathogenic mutation (also known as c.190T>G), located in coding exon 3 of the BRCA1 gene, results from a T to G substitution at nucleotide position 190. The cysteine at codon 64 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation was first described in an African American kindred with multiple cases of early-onset breast and ovarian cancer and segregated with disease (Castilla LH et al. Nat Genet. 1994 Dec;8:387-91). This mutation has also been identified in multiple hereditary breast and ovarian cancer (HBOC) families (Merajver SD et al. Clin Cancer Res, 1995 May;1:539-44; Serova OM et al. Am J Hum Genet, 1997 Mar;60:486-95; Shih HA et al. Clin Cancer Res, 2000 Nov;6:4259-64; Sinilnikova OM et al. Fam Cancer, 2006;5:15-20; Churpek JE et al. Breast Cancer Res Treat, 2015 Jan;149:31-9; Tung N et al. Cancer, 2015 Jan;121:25-33; Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153:201-9; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-6200), as well as in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). in silico studies predict that this alteration will simultaneously disrupt a putative exonic splicing enhancer motif and activate a cryptic 5' splice site in coding exon 4 (Willems P et al. Int. J. Oncol. 2009 Apr;34:1005-15; Mucaki EJ et al. Hum. Mutat. 2011 Jul;32:735-42). This results in a 22-nucleotide partial exon skipping event which is predicted to lead to a truncated protein consisting of only 63 amino acids (Ambry internal data; Yang Y et al. Hum. Mol. Genet 2003 Sep;12:2121-31). Additionally, this alteration has been classified as deleterious by an alternative functional mechanism resulting from disruption of a zinc-binding ring finger residue at this position. Several independent DNA repair assays showed loss of function in p.C64G point mutants for BRCA1 ubiquitin ligase activity, homology directed recombination, functional complementation, and a high-throughput, genome editing, haploid cell survival assay (Scully R et al. Mol Cell, 1999 Dec;4:1093-9; Morris JR et al. Hum. Mol. Genet. 2006 Feb;15:599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lu C et al. Nat Commun 2015 Dec;6:10086; Starita LM et al. Genetics. 2015 Jun;200:413-22; Findlay GM et al. Nature, 2018 10;562:217-222). This alteration is also referred to as 309T>G in published literature. 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 available evidence, this alteration is interpreted as a disease-causing mutation. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Benign

0.67

DEOGEN2

Uncertain

0.48

.;T;.;.;.;.;D;.;.;T;T;D;D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.6

H;H;H;H;.;H;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

N;N;N;D;N;N;D;N;N;.;N;D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;.;D;D;D;.

Sift4G

Uncertain

0.011

D;D;D;D;D;D;.;D;D;.;D;D;.;.

Polyphen

1.0, 1.0

.;D;.;.;.;D;.;.;D;.;.;.;.;.

Vest4

0.97

MutPred

0.99

Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);.;Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);.;Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);Loss of stability (P = 0.0068);.;

MVP

1.0

MPC

0.45

ClinPred

0.77

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.65

Position offset: -22

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over