NM_007294.4:c.463C>G

Variant names:

• chr17-43099859-G-C
• rs80357180
• NM_007294.4:c.463C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.463C>G​(p.Gln155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q155H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: 1.23
• Publications: 21 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13880423).
• BP6: Variant 17-43099859-G-C is Benign according to our data. Variant chr17-43099859-G-C is described in ClinVar as Benign. ClinVar VariationId is 55247.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.463C>G	p.Gln155Glu	missense	Exon 7 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.463C>G	p.Gln155Glu	missense	Exon 7 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.463C>G	p.Gln155Glu	missense	Exon 7 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.463C>G	p.Gln155Glu	missense	Exon 7 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.463C>G	p.Gln155Glu	missense	Exon 7 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.463C>G	p.Gln155Glu	missense	Exon 7 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251438 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460984 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111236

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000232 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Breast-ovarian cancer, familial, susceptibility to, 1 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	16
DANN	Benign	0.39
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.47
Sift	Benign	0.098	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.37
MVP		0.82
MPC		0.087
ClinPred		0.023	T
GERP RS		3.2
Varity_R		0.051
gMVP		0.45
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357180; hg19: chr17-41251876;