rs41293457

Variant names:

• chr17-43074381-G-C
• rs41293457
• NM_007294.4:c.4625C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43074381-G-C
• chr17-43074381-G-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.4625C>G​(p.Ser1542Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1542P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7
• Conservation: PhyloP100: 0.947
• Publications: 20 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2329722).
• BP6: Variant 17-43074381-G-C is Benign according to our data. Variant chr17-43074381-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55242.

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.4625C>G	p.Ser1542Cys	missense	Exon 14 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4691C>G	p.Ser1564Cys	missense	Exon 15 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4691C>G	p.Ser1564Cys	missense	Exon 15 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.4625C>G	p.Ser1542Cys	missense	Exon 14 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4688C>G	p.Ser1563Cys	missense	Exon 15 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4625C>G	p.Ser1542Cys	missense	Exon 14 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251360 AF XY: 0.0000294

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: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33472

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

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
-	2	1	not provided (3)
-	2	1	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Fanconi anemia, complementation group S (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.95
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.42
Sift	Benign	0.075	T
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.21
MVP		0.73
MPC		0.17
ClinPred		0.024	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.039
gMVP		0.16
Mutation Taster		=45/55	disease causing

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: rs41293457; hg19: chr17-41226398;