17-43071017-T-C

Position:

• chr17-43071017-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_007294.4(BRCA1):​c.4897A>G​(p.Ser1633Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20911393).
• BP6: Variant 17-43071017-T-C is Benign according to our data. Variant chr17-43071017-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 865661.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4897A>G	p.Ser1633Gly	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4897A>G	p.Ser1633Gly	missense_variant	15/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1 Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Feb 02, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 14, 2022

Variant summary: BRCA1 c.4897A>G (p.Ser1633Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4897A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Findlay_2018). These results showed no damaging effect of this variant resulting in a "functional" outcome in homology directed repair (HDR). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.090	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.39	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.21	T;T;.;T;.;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;.;.;T
Polyphen		0.17, 0.0050	.;B;.;.;.;.;.;.;B;.
Vest4		0.29
MVP		0.71
MPC		0.078
ClinPred		0.046	T
GERP RS		3.7
Varity_R		0.036
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1555580711; hg19: chr17-41223034;