rs2227945

Variant names:

• chr17-43092113-T-C
• rs2227945
• NM_007294.4:c.3418A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43092113-T-C
• chr17-43092113-T-G
• chr17-43092113-T-A

Variant summary

Our verdict is Benign. The variant received -24 ACMG points: 0P and 24B. BA1 BP5_Strong BP1_Strong BS3 BS2

This summary comes from the ClinGen Evidence Repository: The c.3418A>G variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 1140 (p.Ser1140Gly). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.03171 in the African/African-American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.06, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met). This variant has been observed in more than 10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00029 (based on Co-occurrence LR=0.00029), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID:16014699). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP1_Strong, BS3, BS2, BP5_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA002212/MONDO:0011450/092

• Frequency:
  • Genomes: 𝑓 0.0097 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (21 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:32 O:1
• Conservation: PhyloP100: 0.301
• Publications: 49 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -24 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.3418A>G	p.Ser1140Gly	missense	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.3418A>G	p.Ser1140Gly	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.3418A>G	p.Ser1140Gly	missense	Exon 10 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.3418A>G	p.Ser1140Gly	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.3418A>G	p.Ser1140Gly	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.3418A>G	p.Ser1140Gly	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1476 AN: 152222 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00252 AC: 633 AN: 251092 AF XY: 0.00166

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00105 AC: 1532 AN: 1461540 Hom.: 21 Cov.: 38 AF XY: 0.000873 AC XY: 635 AN XY: 727082

African (AFR) AF: 0.0350 AC: 1172 AN: 33478

American (AMR) AF: 0.00192 AC: 86 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111862

Other (OTH) AF: 0.00217 AC: 131 AN: 60392

GnomAD4 genome AF: 0.00972 AC: 1481 AN: 152340 Hom.: 34 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74506

African (AFR) AF: 0.0341 AC: 1419 AN: 41564

American (AMR) AF: 0.00235 AC: 36 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00375 Hom.: 22

Bravo AF: 0.0105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00311 AC: 377

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	7	Breast-ovarian cancer, familial, susceptibility to, 1 (8)
-	-	7	not specified (8)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	1	BRCA1-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.30
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.069
Sift	Benign	0.32	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.21
MVP		0.52
MPC		0.083
ClinPred		0.0094	T
GERP RS		1.6
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.057
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.060		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: rs2227945; hg19: chr17-41244130; COSMIC: COSV58797608; COSMIC: COSV58797608;