17-43104222-G-C

Variant names:

• chr17-43104222-G-C
• rs786202620
• NM_007294.4:c.341C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001407959.1(BRCA1):​c.-41C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,460,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_001407959.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 3.81
• Publications: 9 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407959.1. 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.341C>G	p.Ser114Cys	missense	Exon 6 of 23	NP_009225.1
	BRCA1	NM_001407959.1		c.-41C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 20	NP_001394888.1
	BRCA1	NM_001407960.1		c.-41C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 21	NP_001394889.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.341C>G	p.Ser114Cys	missense	Exon 6 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.341C>G	p.Ser114Cys	missense	Exon 6 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.341C>G	p.Ser114Cys	missense	Exon 6 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460524 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726654

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110902

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.44		Loss of disorder (P = 0.0276)
MVP		0.93
MPC		0.42
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.21
gMVP		0.49

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

Other links and lift over

dbSNP: rs786202620; hg19: chr17-41256239;