rs80357370

Variant names:

• chr17-43106529-A-C
• rs80357370
• NM_007294.4:c.139T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43106529-A-C
• chr17-43106529-A-G
• chr17-43106529-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_007294.4(BRCA1):​c.139T>G​(p.Cys47Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,876 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. C47Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.84
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 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 chr17-43106528-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54246.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-43106529-A-C is Pathogenic according to our data. Variant chr17-43106529-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54242.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.139T>G	p.Cys47Gly	missense_variant	Exon 4 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.139T>G	p.Cys47Gly	missense_variant	Exon 4 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435876 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 715670

African (AFR) AF: 0.00 AC: 0 AN: 32884

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.00 AC: 0 AN: 85060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5400

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089788

Other (OTH) AF: 0.00 AC: 0 AN: 59430

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1

May 13, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.139T>G (p.Cys47Gly) variant involves the alteration of a conserved nucleotide resulting in a replacement of a conserved canonical Cysteine residue of the BRCA1 RING domain with a Glycine. Cysteine residues are known to be essential for Zn ion coordination and for proper folding of the RING domain of the BRCA1 protein (PMID: 11573085). Mutations of these Cysteine residues are known to be clinically relevant, and predispose individuals to cancer (BIC, HGMD). Consistently, 5/5 in silico tools predict this variant to be deleterious. Furthermore, it is absent in 111676 control chromosomes. It was reported in one early onset TNBC patient further supporting its pathogenicity. Multiple independent functional studies have demonstrated that this variant results in loss of homology directed repair activity of BRCA1 in addition to a loss of E3 ubiquitin ligase activity as well as its ability to bind to the UbcH5a protein. A congruence of multiple functional studies further supports a disease causing impact for this variant. Two databases classify variant as Pathogenic (UMD, HGMD). Moreover, BIC, HGMD, ClinVar list variants affecting the same codon as the variant of interest (C47F, C47Y, C47X) as pathogenic indicating the variant to be located in a mutational hotspot and further supporting a disease causing impact. Considering all available lines of evidence, the variant is classified as a Probably Disease causing (i.e., Likely Pathogenic) variant in the BRCA1 gene. -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1

-

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;T;.;.;.;D;.;T;T;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;H;H;H;.;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;N;N;D;N;D;N;.;N;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;.;D;.;D;D;.
Polyphen		0.99, 1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.
Vest4		0.97
MutPred		0.97		Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);
MVP		1.0
MPC		0.24
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs80357370; hg19: chr17-41258546;