NM_007294.4:c.3600G>C

Variant names:

• chr17-43091931-C-G
• rs56214134
• NM_007294.4:c.3600G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007294.4(BRCA1):​c.3600G>C​(p.Gln1200His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,614,128 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1200E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 0.672
• 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):

• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02793637).
• BP6: Variant 17-43091931-C-G is Benign according to our data. Variant chr17-43091931-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 54930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.3600G>C	p.Gln1200His	missense	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.3600G>C	p.Gln1200His	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.3600G>C	p.Gln1200His	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.3600G>C	p.Gln1200His	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.3600G>C	p.Gln1200His	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.3600G>C	p.Gln1200His	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 250966 AF XY: 0.000177

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461796 Hom.: 1 Cov.: 33 AF XY: 0.000114 AC XY: 83 AN XY: 727180

African (AFR) AF: 0.00451 AC: 151 AN: 33476

American (AMR) AF: 0.0000895 AC: 4 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111978

Other (OTH) AF: 0.000149 AC: 9 AN: 60390

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152332 Hom.: 2 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74484

African (AFR) AF: 0.00423 AC: 176 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00119

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not specified (4)
-	-	1	BRCA1-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.67
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.041	D
Polyphen		0.21	B
Vest4		0.49
MutPred		0.30		Loss of MoRF binding (P = 0.0854)
MVP		0.50
MPC		0.23
ClinPred		0.050	T
GERP RS		1.2
PromoterAI		0.013	Neutral
Varity_R		0.093
gMVP		0.19
Mutation Taster		=83/17	polymorphism

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: rs56214134; hg19: chr17-41243948;