17-43093324-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):c.2207A>C(p.Glu736Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E736K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.274

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14755723).
• BP6: Variant 17-43093324-T-G is Benign according to our data. Variant chr17-43093324-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 37455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43093324-T-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2207A>C	p.Glu736Ala	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2207A>C	p.Glu736Ala	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461240 Hom.: 0 Cov.: 42 AF XY: 0.00000138 AC XY: 1 AN XY: 726936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2024	Variant summary: BRCA1 c.2207A>C (p.Glu736Ala) 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 250714 control chromosomes (gnomAD v2, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2207A>C has been reported in the literature in an individual with an unspecified cancer diagnosis without evidence of cosegregation (Kurian_2008), and also, in a breast cancer tumor where it was interpreted as neutral by the authors (Spearman_2008). A publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of likely benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of breast tumor pathology, co-occurrence, family history and bioinformatic predictions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 29580235, 18779604, 21990134, 22753008, 31131967, 18824701). ClinVar contains an entry for this variant (Variation ID: 37455). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	This variant is associated with the following publications: (PMID: 22753008, 21990134, 24728327, 18824701, 18779604, 31131967) -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 19, 2016	- -

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

Benign, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

Feb 01, 2012

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Glu736Ala variant was identified in the literature and classified using a multifactorial probability based model as likely benign, however the frequency of this variant in an affected population was not provided (Lindor_2012_21990134). The variant was also identified in dbSNP (ID: rs397507196) as “With Likely benign allele”, ClinVar (as likely benign by Ambry, GeneDx, Invitae, and ARUP, and as benign by SCRP), Clinvitae (4x), GeneInsight-COGR, LOVD 3.0 (2x), ARUP Laboratories (as likely benign) databases. The variant was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 30964 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 1 of 1620 chromosomes (freq: 0.000617), while the variant was not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, European (Finnish) and South Asian populations. The p.Glu736 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	4.5
Dann	Benign	0.86
DEOGEN2	Uncertain	0.48	T;.;.;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.9	D;D;D;D;.
REVEL	Uncertain	0.45
Sift	Benign	0.13	T;T;T;T;.
Sift4G	Benign	0.27	T;T;T;T;.
Polyphen		0.046	B;.;.;B;.
Vest4		0.23
MutPred		0.29		Loss of methylation at K734 (P = 0.0711);Loss of methylation at K734 (P = 0.0711);.;Loss of methylation at K734 (P = 0.0711);.;
MVP		0.48
MPC		0.16
ClinPred		0.10	T
GERP RS		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.076

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507196; hg19: chr17-41245341;