17-43070958-C-T

Variant names:

• chr17-43070958-C-T
• rs1799967
• NM_007294.4:c.4956G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.4956G>A​(p.Met1652Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,160 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1652R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.015 (312 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:41 O:1
• Conservation: PhyloP100: 1.31
• Publications: 126 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):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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 -16 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 78 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43070958-CA-TT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 665843.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070306957).
• BP6: Variant 17-43070958-C-T is Benign according to our data. Variant chr17-43070958-C-T is described in ClinVar as Benign. ClinVar VariationId is 41830.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0138 (2106/152288) while in subpopulation SAS AF = 0.0323 (156/4830). AF 95% confidence interval is 0.0282. There are 26 homozygotes in GnomAd4. There are 1188 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4956G>A	p.Met1652Ile	missense	Exon 15 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5022G>A	p.Met1674Ile	missense	Exon 16 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5022G>A	p.Met1674Ile	missense	Exon 16 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4956G>A	p.Met1652Ile	missense	Exon 15 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5019G>A	p.Met1673Ile	missense	Exon 16 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4956G>A	p.Met1652Ile	missense	Exon 15 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2104 AN: 152170 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0180 AC: 4515 AN: 250924 AF XY: 0.0202

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0515

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0147 AC: 21500 AN: 1461872 Hom.: 312 Cov.: 31 AF XY: 0.0158 AC XY: 11467 AN XY: 727236

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.00461 AC: 206 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 599 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0361 AC: 3113 AN: 86258

European-Finnish (FIN) AF: 0.0484 AC: 2587 AN: 53406

Middle Eastern (MID) AF: 0.0241 AC: 139 AN: 5768

European-Non Finnish (NFE) AF: 0.0125 AC: 13948 AN: 1112006

Other (OTH) AF: 0.0139 AC: 839 AN: 60394

GnomAD4 genome AF: 0.0138 AC: 2106 AN: 152288 Hom.: 26 Cov.: 32 AF XY: 0.0160 AC XY: 1188 AN XY: 74482

African (AFR) AF: 0.00188 AC: 78 AN: 41552

American (AMR) AF: 0.00425 AC: 65 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4830

European-Finnish (FIN) AF: 0.0555 AC: 588 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1104 AN: 68026

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0145 Hom.: 73

Bravo AF: 0.00878

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0152 AC: 131

ExAC AF: 0.0176 AC: 2139

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0151

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	12	Breast-ovarian cancer, familial, susceptibility to, 1 (14)
-	-	11	not specified (12)
-	-	6	not provided (6)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	1	4	Hereditary cancer-predisposing syndrome (5)
-	-	1	BRCA1-related cancer predisposition (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.17	N
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.43
Sift	Benign	0.32	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.091
ClinPred		0.0072	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.30
Mutation Taster		=69/31	polymorphism (auto)

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: rs1799967; hg19: chr17-41222975; COSMIC: COSV58787197;